Yanling
Shen
,
Ning
Lei
,
Cong
Lu
,
Dailin
Xi
,
Xinxin
Geng
,
Pan
Tao
,
Zhishan
Su
and
Ke
Zheng
*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, P. R. China. E-mail: kzheng@scu.edu.cn
First published on 17th November 2021
The oxindole scaffold represents an important structural feature in many natural products and pharmaceutically relevant molecules. Herein, we report a visible-light-induced modular methodology for the synthesis of complex 3,3′-disubstituted oxindole derivatives. A library of valuable fluoroalkyl-containing highly sterically congested oxindole derivatives can be synthesized by a catalytic three-component radical coupling reaction under mild conditions (metal & photocatalyst free, >80 examples). This strategy shows high functional group tolerance and broad substrate compatibility (including a wide variety of terminal or non-terminal alkenes, conjugated dienes and enynes, and a broad array of polyfluoroalkyl iodide and oxindoles), which enables modular modification of complex drug-like compounds in one chemical step. The success of solar-driven transformation, large-scale synthesis, and the late-stage functionalization of bioactive molecules, as well as promising tumor-suppressing biological activities, highlights the potential for practical applications of this strategy. Mechanistic investigations, including a series of control experiments, UV-vis spectroscopy and DFT calculations, suggest that the reaction underwent a sequential two-step radical-coupling process and the photosensitive perfluoroalkyl benzyl iodides are key intermediates in the transformation.
Fluorine-containing groups in organic molecules serve as versatile and valuable motifs in the agrochemical industry, medicinal chemistry and materials science, and have the potential to exert profound changes in the lipophilicity, solubility, metabolic stability, and bioavailability properties of molecules in drug discovery.7 The iodoperfluoroalkylation of olefins is an efficient transformation for accessing this class of compounds relying on the use of photochemistry, in which the commercially available perfluoroalkyl halides (Rf–X) were used as powerful and versatile precursors to generate electrophilic perfluoroalkyl radicals.8 Numerous elegant reports of photocatalytic iodoperfluoroalkylation of alkenes using organic bases or photocatalysts have been well established.9 However, for most of them, the radical acceptors were limited to alkyl alkenes, and only a limited number of analogous transformations have been reported for conjugated alkenes (Scheme 1C).10 This was likely to originate from the instability of conjugated carbon radical intermediates,11,12 or iodoperfluoroalkylation products such as sensitive benzyl iodides, especially the tertiary benzyl iodides with steric hindrance.10a,13 We questioned whether or not such unstable, photosensitive benzyl iodides could be used as intermediates for the next transformations by secondary excitation under irradiation. If it works, it should be possible to design a sequential multistep radical-coupling process to construct functionally and structurally diverse products from ubiquitous starting materials under mild conditions.
Continuing our interest in developing new photochemical methods,14 we present herein visible-light-driven highly selective three-component radical coupling reactions for the construction of fluoroalkyl-containing highly sterically congested oxindole derivatives in a single step, which would require multistep syntheses using other methods (>80 examples, Scheme 1D). This transformation could successfully be applied to a wide variety of conjugated alkenes, including terminal or non-terminal styrene derivatives, dienes and enynes. The potential efficacy of this new approach was evidenced by the success of gram-level synthesis, late-stage functionalization, and modular modification of known bioactive pharmaceuticals.
Entry | Variation from standard conditions | Yieldb% |
---|---|---|
a Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), 3a (0.2 mmol) and DIPEA (0.2 mmol) in THF (1.0 mL) were irradiated with 10 W white LEDs under N2 at 25 °C. b Yield of the isolated product; dr (diastereomeric ratio) of product was 1:1. c Reaction time: 4 h. DIPEA = N,N-diisopropylethylamine. | ||
1 | None | 88 |
2 | 395 nm LED | 75 |
3 | 525 nm LED | Trace |
4 | DMF as solvent | 69 |
5 | CH3OH as solvent | 66 |
6 | Cs2CO3 instead of DIPEA | 43 |
7 | K2CO3 instead of DIPEA | 73 |
8 | Aniline instead of DIPEA | Trace |
9 | 0.2 M or 0.05 M | 77 |
10 | Heat to 40 °C | 88c |
11 | Without DIPEA | Trace |
12 | In air or without light | Trace |
With the optimized reaction conditions in hand, we first explored the scope of 3-substituted oxindoles (Table 2). Remarkably, the reaction proved suitable for the synthesis of highly sterically congested quaternary centers even in good to excellent yields (5–29). The reactions performed well with a variety of 3-aryl substituted oxindoles with electron-neutral, electron-donating, and electron-withdrawing substituents, giving the corresponding products in excellent yields (5–16). The oxindole with 4-substituents on the aromatic ring produced the products with slightly lower yield (5) due to its steric crowding adjacent to the reactive site. Substituents on the aromatic ring of the 3-aryl oxindole with a variety of functional groups afforded the product in good to excellent yields (17–25). To our delight, 3-heterocyclic- and 3-naphthyl- substituted oxindoles were also well tolerated under optimized conditions (26 and 27). The substituted group on the nitrogen of oxindoles does not affect the outcome (86%, 28), and benzofuranone gave the desired product in high yield (95%, 29).
Having established a broad scope for oxindoles, our attention was turned to the scope with respect to alkenes. As shown in Table 3, both simple and functionalized alkenes were good coupling partners under these conditions (30–66). Substituted styrenes with electron-donating and electron-withdrawing groups gave the corresponding products in good yields (30–36). Even more electron-deficient pentafluoro-substituted styrene (37) could be used effectively, producing the desired product in moderate yield. 2-Vinylnaphthalene and 9-vinylanthracene underwent the reaction smoothly to give the corresponding products in high yields (38 and 39). The boronic acid (40) and carboxyl group (41) were well tolerated, thus making this protocol suitable for synthesis of oxindole derivatives without protective groups. Disubstituted alkenes were also well-tolerable with excellent yields (42–43). Additionally, the product 43 gave a higher dr value (10:1) due to its steric hindrance. Heterocyclic olefins gave the products in moderate yields due to the lability of the heterocyclic system (44–45). Notably, the reaction could accommodate thiophene ethylene, and a mixture of 1,2-addition and 1,6-addition products was observed in acceptable yield (46). To our delight, a wide range of highly functionalized 1,1-disubstituted alkenes such as α-bromo (47), α-boronic ester (48), α-trifluoromethyl (49), and α-carboxyl (50) could be successfully used in this radical-based process to give three-component coupling products in synthetically useful yields, and an excellent dr was obtained for product 50 (dr > 20:1), opening avenues for further synthetic operations. Meanwhile, a highly selective reaction occurred at the aryl alkene position of the substrate, which contained both an aryl alkene and an alkyl alkene moiety, to obtain an exclusive product in excellent yield (51). Non-terminal styrenes such as 1,2-dihydronaphthalene (52), 1-cyclobuten-1-ylbenzene (53), and 1H-indene (54) also performed well to give congested products in moderate yields.
a Reaction conditions: 1 (0.1 mmol), 2a (0.2 mmol), 3a (0.2 mmol), and DIPEA (0.2 mmol) in THF (1.0 mL) were irradiated with 10 W white LEDs under N2 at 40 °C. Yield of the isolated product. The dr (diastereomeric ratio) of the product was 1:1 unless otherwise noted. b dr = 2:3. c dr = 10:1. d Detected by 1H NMR, Z:E = 2:1 (1,6 addition). e dr = 4:1. f dr > 20:1. g dr = 5:2:3. |
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It was worth noting that conjugate olefins such as 1,3-dienes (55–57) proved to be competent partners in the reaction, highlighting the extraordinary substrate scope of this strategy. When 1,3-butadiene and cyclohexa-1,3-diene were subjected to this protocol, a mixture of 1,2-addition and 1,4-addition products was obtained in high yields (55 and 56), while only 1,4-addition product 57 was obtained for 2,3-dimethylbuta-1,3-diene. Notably, 1,3-enynes could also be used as radical acceptors to form substituted allenyl (1,4-adducts) or alkynyl (1,2-adducts) derivatives under the optimized conditions, which are important structural motifs found in pharmaceuticals and considered as key intermediates in the synthesis of complex molecules. Compared to the product mixture obtained with 2-methyl substituted enynes (58 and 59), 2-phenyl substituted enynes gave the 1,4-addition product allenes (60 and 61) in excellent yields exclusively. The excellent functional group compatibility and broad substrate scope of this strategy encouraged us to evaluate its application in the late-stage functionalization of bioactive molecules. Several drugs and natural product derivatives such as isoeugenol, estrone, menthol, flavanone and galactose were subjected to the optimized reaction conditions, resulting in the desired complex products in good to excellent yields (62–66).
To illustrate the utility of this new transformation with respect to drug discovery, we applied this radical three-component coupling reaction to modify p53 inhibitor II (Roche). Using a variety of polyfluoroalkyl halides as the fluorinating reagent, a series of polyfluorinated analogues (67–78) of inhibitor II were furnished in high yields under mild conditions (Table 4). The estrogen derivatives were also tolerable in our system to deliver corresponding products in good yields after a two-step reaction (79–82). The success of sunlight-driven transformation (78, 84% yield) and gram-scale synthesis (78, 1.05 g, 65% yield) revealed the potential of this strategy in industrial applications (for more details see ESI, Fig. S6†). To demonstrate the biological application of these analogues, some of the polyfluorinated oxindole derivatives were assayed for growth inhibitory activities on the human cancer cell line MCF-7 (breast cancer); compared to p53 inhibitor II, the anti-tumor activity of fluorine-modified compounds was significantly improved (Table 5 and S5†). Further SAR of these new scaffolds is currently in progress in our groups.
a Reaction conditions: 1b (0.1 mmol), 2 (0.2 mmol), 3a (0.2 mmol), and DIPEA (0.2 mmol) in THF (1.0 mL) were irradiated with 10 W white LEDs under N2 at 40 °C. Yield of the isolated product. The dr (diastereomeric ratio) of the product was 1:1. b Two steps, see the ESI† for exact experimental procedures. |
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Compounds | p53 inhibitor II | 32 | 56 | 68 | |
IC50 (MCF-7) | 38.95 | 21.16 | 21.99 | 16.73 | |
Compounds | 69 | 70 | 71 | 72 | 76 |
IC50 (MCF-7) | 22.63 | 7.23 | 20.60 | 21.04 | 20.99 |
Having established a broad scope for the synthesis of polyfluorinated oxindole derivatives, our attention was focused on the mechanism of this three-component radical-coupling reaction. UV-vis spectroscopic measurements on various combinations of 1b, 2b, and 3a with different bases were first performed. Compared to the marked yellow color and red-shift of the UV-vis absorption observed by using strong bases such as Cs2CO3 or DUB as additives (the Rf˙ was initiated by the photoconductive EDA complex of enolate with C4F9I, see Fig. S7 and S8†), no color change and no detectable red-shift with a mixture of DIPEA, 1b and C4F9I were observed. These results indicated that the possibility of the EDA complex of substrates with DIPEA as the base additive was excluded (for more control experiments see ESI, Tables S6 and S7†). Moreover, the iodoperfluoroalkylation product 85 was obtained during the reaction course, even without oxindole under the standard conditions (Scheme 2a). We monitored this process by 1H NMR and found that benzyl iodide 85 was unstable and would rapidly decompose under white light irradiation (see ESI, Fig. S9†). This outcome was different from Reiser's work, in which the iodoperfluoroalkylation product 85 can be obtained in high yield due to its stability under green light.10 Meanwhile, the results of light on/off experiments suggested that the formation of 85 did not occur by the chain process (see ESI, Fig. S9†), which was consistent with the previous reports.10a,15 We considered that in our process, this unstable, photosensitive benzyl iodide 85 might be the key intermediate for the next coupling step.
To gather direct experimental evidence, the intermediate 85 was synthesized and subjected to the optimized reaction conditions. To our delight, compound 85 showed a noticeable reactivity toward 1b and product 30 was obtained in good yield with 10% dimerization product 83 of oxindole. In the absence of light, compared to the high yield obtained with K2CO3 (SN2 addition), only a trace amount of the desired product 30 was detected in the presence of DIPEA at 80 °C in the dark for 8 h (Scheme 2b),16 indicating that 1b and 85 were more likely to undergo a radical coupling process than a nucleophilic process under standard conditions. Additionally, the benzyl radical captured product 86 was obtained in 83% yield (Scheme 2c) when the radical scavenger TEMPO and 85 were irradiated directly in THF. These results provided a piece of direct evidence for the formation of the benzyl radical and I˙ radical as key intermediates by homolysis of the C–I bond of photosensitive benzyl iodide 85 under irradiation during the transformation, as well as the reaction undergoing a radical-coupling pathway. These can also explain why a low yield was observed for the iodoperfluoroalkylation product 85 in Scheme 2a (due to the photolysis of 85 under light irradiation).
After demonstrating that iodoperfluoroalkylation product 85 was a key intermediate during the transformation, subsequent efforts were aimed at confirming the essential HAT substance that formed the oxindole radical in the HAT process (Scheme 3a and b). The two possible HAT reagents for abstracting the hydrogen atom from the oxindole as described here were DIPEA˙+ (from photoexcitation of the XB adduct of DIPEA and C4F9I) and I˙ (from homolysis of photosensitive intermediate 85). As shown in Scheme 3a, no dimerization product 83 was observed when the mixture of oxindole 1b and C4F9I was subjected to the optimized reaction conditions, indicating that DIPEA˙+ was not a HAT reagent in our strategy. This was further supported by the DFT calculation of radical I˙ with a lower energy barrier in the HAT process (6.6 kcal mol−1 for I˙ vs. 33.9 kcal mol−1 for DIPEA˙+). The radical clock experiment of α-cyclopropylstyrene 2d gave the ring-opening product 87 in 87% yield with no dimerization product 83, suggesting that no radical I˙ was produced in the transformation because the product 87 was stable under light irradiation (Scheme 3b). This was further supported by DFT calculations.17 Together with DFT calculations and control experiments, we considered that the I˙ radical was the HAT reagent in this process, which was generated from the photolysis of photosensitive intermediate 85.
Based on the above mechanistic results and previous reports, the proposed mechanism for the radical three-component coupling reaction is depicted in Scheme 3. Upon visible-light irradiation, the XB (halogen bond) complex of DIPEA and perfluoroalkyl iodide 3 is excited and generates the fluoroalkyl radical Rf˙ and complex A (DIPEA˙+I−).9f,i,18 The fluoroalkyl radical Rf˙ adds to the olefin 2 to form a new radical, which reacts with complex A, leading to the key photosensitive intermediate C (iodoperfluoroalkylation product). The iodine radical I˙ and radical D are generated by photolysis of intermediate C under light irradiation. The resulting radical I˙ acts as a HAT reagent, abstracting the hydrogen atom from oxindole 1 to generate the persistent oxindole radical E. Finally, the combination of the radical D with the oxindole radical E affords the three-component coupling product F.
Footnote |
† Electronic supplementary information (ESI) available: Detailed experimental procedures, computational details, and spectroscopic data for all new compounds. CCDC 2090721, 2096415 and 2096414. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1sc05273j |
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