Solvent-free iodine-promoted synthesis of 3,2&

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Jun 4, 2018 - milled with benzylamine 5a in the presence of a catalytic amount (10 ... reaction of alkylidene oxindoles with enamino esters via an iodine-.

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Cite this: Chem. Commun., 2017, 53, 12477 Received 27th October 2017, Accepted 30th October 2017 DOI: 10.1039/c7cc08306h

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Solvent-free iodine-promoted synthesis of 3,2 0 -pyrrolinyl spirooxindoles from alkylidene oxindoles and enamino esters under ball-milling conditions† Hui Xu,

a

Hong-Wei Liu,a Hao-Sheng Lin

a

and Guan-Wu Wang

*ab

rsc.li/chemcomm

A novel solvent-free iodine-promoted cyclization of alkylidene oxindoles with enamino esters via C–C/C–N bond formation has been demonstrated under ball-milling conditions. This protocol provides efficient and green access to a variety of 3,2 0 -pyrrolinyl spirooxindoles with remarkable functional group tolerance, good yields and excellent diastereoselectivities.

Nitrogen-containing spirocyclic oxindoles are prevalent frameworks in numerous natural products and bioactive molecules, and exhibit a broad spectrum of significant bioactivities such as antimitotic, anti-inflammatory, antibacterial, antimicrobial and antimycobacterial activities (Fig. 1).1 Accordingly, spirooxindoles have been widely applied in medicinal chemistry.2 As a consequence, considerable efforts have been devoted to the construction of these heterocyclic motifs, and several synthetic methods have been established.3 Among them, [3+2] cycloaddition reactions are the most commonly used approaches.4 Nevertheless, these reactions often suffer from some drawbacks, such as the use of organic solvents and long reaction times. In addition, 3,2 0 -pyrrolinyl spirooxindoles, a kind of important spirooxindole, have been rarely investigated.5 Therefore, the development of greener and more efficient strategies towards highly substituted 3,2 0 -pyrrolinyl spirooxindoles is of great importance and highly desirable. On the other hand, solvent-free chemical synthesis provides environmentally friendly protocols and has aroused increasing interest in recent years. Among the current solvent-free techniques, ball-milling is an attractive and practical tool to implement a

CAS Key Laboratory of Soft Matter Chemistry, iChEM (Collaborative Innovation Center of Chemistry for Energy Materials), Hefei National Laboratory for Physical Sciences at Microscale, and Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China. E-mail: [email protected]; Fax: +86 551 3607864; Tel: +86 551 3607864 b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, P. R. China † Electronic supplementary information (ESI) available: Experimental procedures and NMR spectra. CCDC 1557956. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7cc08306h

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Fig. 1

Representative bioactive spirocyclic oxindoles.

solvent-free reactions,6 especially for insoluble reactants, and can increase the reaction rate or product yield significantly in many cases. In addition, the mechanochemical protocols can even alter the chemical reactivity and selectivity compared to the analogous solution-based reactions, leading to different products or equilibrium mixtures.7 Therefore, the ball-milling technique has been extensively utilized in the fields of synthetic chemistry and materials science.8 Meanwhile, molecular iodine (I2) as an efficient and environmentally benign reagent/catalyst has been widely applied in organic synthesis because of its low cost compared to the transition-metal catalysts, high tolerance to air and moisture, and abundant availability.9,10 Recently, Li’s group reported a novel and interesting I2-promoted tandem reaction of chalcones with enamines for efficient synthesis of a variety of 2,3-dihydropyrroles.11 Inspired by this work, the abovementioned importance of spirocyclic oxindoles and the great potential of mechanochemistry in organic synthesis, we attempted to construct 3,2 0 -pyrrolinyl spirooxindoles via a Michael/cyclization of alkylidene oxindoles with enamino esters promoted by I2 under solvent-free ball-milling conditions. It should be stressed that this is the first attempt of I2-promoted tandem Michael/cyclization on alkylidene oxindoles. The reaction of alkylidene oxindole 1a with enamine ester 2a was chosen as the model reaction to determine the optimal

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Table 1

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Selected optimization of the reaction conditionsa

Table 2 I2-Promoted reactions of alkylidene oxindoles 1a–o with enamino ester 2a under ball-milling conditionsa,b

Entry Molar ratio (1a : 2a : I2) Base (equiv.)

Time (h) Yieldb (%)

1 2 3c 4c 5d 6e 7f

0.5 1 1 1 5 3 10

1:1:1 1:2:1 1:2:1 1:2:1 1:2:1 1:2:1 1:2:1

— — — DABCO6H2O DABCO6H2O DABCO6H2O DABCO6H2O

(0.5) (0.5) (0.5) (0.5)

32 52 63 74 71 67 35

a

Unless otherwise noted, the reactions were carried out in a Spex SamplePrep 5100 mixer mill with 0.2 mmol of 1a. b Isolated yield based on 1a. c 200 mg of silica gel (200–300 mesh) was employed as the milling auxiliary. d The reaction was performed in 1,2-dichloroethane (2 mL) at 50 1C for 5 h. e The reaction was performed in acetonitrile (2 mL) at 50 1C for 3 h. f The reaction was performed in toluene (2 mL) at 50 1C for 10 h.

reaction conditions (see Table 1 for selected screening conditions and the ESI† for details). At first, a mixture of 1a (0.2 mmol), 2a (0.2 mmol) and I2 (0.2 mmol) was milled vigorously (50 Hz) in a Spex SamplePrep 5100 mixer mill at room temperature for 0.5 h, and the desired product 3,20 -pyrrolinyl spirooxindole 3aa was isolated in 32% yield (Table 1, entry 1). Upon increasing the amount of 2a to 2 equiv. and extending the reaction time to 1 h, the yield of product 3aa was increased to 52% (entry 2). The yield of 3aa could be further improved to 63% by adding 200 mg of silica gel (200–300 mesh) as a milling auxiliary (entry 3). Considering that HI was formed during this process, we speculated that the introduction of a base would be beneficial to this transformation. To our delight, 0.5 equiv. of 1,4-diazobicyclo[2,2,2]octane hexahydrate (DABCO6H2O) could facilitate this transformation, affording the desired product in 74% yield (entry 4). For the purpose of comparing the present solvent-free reaction and its liquid-phase counterpart, the reaction was also carried out in several organic solvents including 1,2-dichloroethane (DCE), acetonitrile and toluene at 50 1C (entries 5–7). The results demonstrated that DCE was the most effective solvent, and afforded 3aa in 71% yield after a reaction time of 5 h (entry 5). From these results, it can be obviously found that the mechanochemical protocol has remarkable advantages, including shorter reaction time, higher yield and an easier work-up procedure. Thus, the optimal reaction conditions were as follows: 1a (0.2 mmol), 2 equiv. of 2a, 1 equiv. of I2, 0.5 equiv. of DABCO6H2O and 200 mg of silica gel under solvent-free ball-milling conditions for 1 h (entry 4). With the optimized reaction conditions in hand, we then examined the scope and generality of this reaction. Firstly, various oxindole derivatives were allowed to react with enamino ester 2a under the standard conditions (Table 2). From Table 2, it can be seen that oxindoles 1 with the phenyl ring bearing either electron-donating or withdrawing groups reacted smoothly with 2a, affording a series of spirocyclic oxindoles 3ba–ga in moderate to good yields (57–82%). Notably, oxindoles

12478 | Chem. Commun., 2017, 53, 12477--12480

a The reactions were performed with 1 (0.2 mmol), 2a (0.4 mmol), I2 (0.2 mmol), DABCO6H2O (0.1 mmol) and silica gel (200–300 mesh, 200 mg) together with 8 stainless balls (5 mm in diameter) in a Spex SamplePrep 5100 mixer mill for 1 h. b Isolated yields based on 1. Diastereomeric ratio (dr) was determined by 1H NMR spectroscopy.

bearing electron-donating groups exhibited a relatively higher efficiency (3ba, 3ca, 3fa and 3ga vs. 3da and 3ea). When the ethyl ester was replaced by the methyl or tert-butyl ester in the oxindoles, the desired products 3ha and 3ia were achieved in 70% and 72% yields, respectively. Both acyl and alkyl groups at the nitrogen atom in oxindoles 1 reacted well and afforded 3ja–na in 54–70% yields. Intriguingly, unprotected oxindole 1o was also applicable in this reaction to afford the corresponding product 3oa in 63% yield. To further explore the substrate scope, various enamino esters (2b–p) were investigated, and the results are illustrated in Table 3. Gratifyingly, all the employed enamino esters with alkyl or phenyl substituents at the nitrogen atom were compatible under the optimized ball-milling conditions, and the corresponding products 3bb–bj were obtained in good yields (66– 83%). Meanwhile, the spirooxindoles 3bk–bm were also isolated in good yields of 75–79% by varying the ester groups of the enamines. Moreover, when the methyl group of enamines 2 was replaced by the ethyl, isopropyl or phenyl group, the corresponding products 3bn–bp could be obtained in 48–74% yields. All the obtained spirooxindoles 3 were unambiguously determined by 1H NMR, 13C NMR and HRMS (ESI). Furthermore, the stereochemistry of products 3 was clearly established

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Table 3 I2-Promoted reaction of alkylidene oxindole 1b with enamino esters 2b–p under ball-milling conditionsa,b

a The reactions were performed with 1b (0.2 mmol), 2 (0.4 mmol), I2 (0.2 mmol), DABCO6H2O (0.1 mmol) and silica gel (200–300 mesh, 200 mg) together with 8 stainless balls (5 mm in diameter) in a Spex SamplePrep 5100 mixer mill for 1 h. b Isolated yields based on 1b. Diastereomeric ratio (dr) was determined by 1H NMR spectroscopy. c 0.3 mmol of I2 and 0.2 mmol of DABCO6H2O were used.

by single-crystal X-ray diffraction analysis of 3bm as an example (Fig. 2), showing that the amide moiety at the spiro carbon and the ester group at C9 were in the trans-form. The angle between the oxindole plane and the N2–C7–C9 plane was 86.96 degrees, with N2 and C9 being almost evenly distributed on both sides of the oxindole plane. In addition, the diastereomeric ratio (dr) for spirooxindoles 3aa–oa and 3bb–bm was determined by comparing the integral of the CH3 peak on the dihydropyrrole moiety (H16 as shown in Fig. 2) of the major isomers (transform) with that of the minor isomers (cis-form) in their 1H NMR spectra, the dr for 3bn–bp was determined according to the

Fig. 2

Single-crystal X-ray structure of compound 3bm.

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integral of the CH3 peak in the oxindole moiety. All products 3 were achieved with high diastereoselectivity (492 : 8 dr), and spirooxindoles 3da–fa, 3ja–na, 3bb, 3bc, 3bi, 3bj, 3bl and 3bp were even formed as a single diastereoisomer.12 Given that the enamino esters might be synthesized under ball-milling conditions,13 a one-pot two-step synthesis of spirocyclic oxindole 3ba was carried out in the ball mill (Scheme 1). In a representative experiment, ethyl acetoacetate 4a was firstly milled with benzylamine 5a in the presence of a catalytic amount (10 mol%) of I2 for 0.5 h to generate 2a, and then 1b, I2, DABCO6H2O and silica gel were added and milled vigorously under the above-mentioned conditions. As expected, the target compound 3ba was obtained in a satisfactory yield of 73%, slightly lower than that (82%) starting directly from the enamino ester. It could be pointed out that a one-pot three-component reaction of 1b, 4a and 5a without stepwise operation led to a complicated mixture. Therefore, the synthesis of the spirocyclic oxindoles 3 could also be achieved using the above one-pot two-step process with b-ketoester, amine and alkylidene oxindoles as the starting materials. Based on the above experimental results and previous literature,11,14 we propose a plausible mechanism (Scheme 2). The reaction begins with a Michael addition between oxindole 1 and enamino ester 2 in the presence of I2 to give intermediate A (determined by HRMS, ESI).15 Then, A reacts with I2 to generate iodide B. During this transformation, a molar equivalent of HI is formed and further captured by DABCO. Subsequently, an intramolecular SN2-type nucleophilic substitution takes place with the elimination of HI, which is captured by DABCOHI, affording product 3 with the amide moiety at the spiro carbon and the ester group at C9 in the trans-form. During the whole process, a total of 2.0 equiv. of HI is formed, and besides HI being captured by DABCO and DABCOHI, HI may also be captured by enamino ester 2, thus explaining why an excess amount of 2 is required to achieve higher product yields. In summary, we have successfully developed a novel solvent-free reaction of alkylidene oxindoles with enamino esters via an iodinepromoted tandem Michael/cyclization sequence under ball-milling conditions, affording a variety of spirocyclic oxindoles in moderate to good yields with excellent diastereoselectivity. This efficient and environmentally benign protocol features short reaction time, mild reaction conditions, good functional group tolerance and a facile work-up procedure. These merits make the present method a new alternative to the practical synthesis of highly substituted 3,2 0 -pyrrolinyl spirooxindoles. We are grateful for financial support from the National Natural Science Foundation of China (No. 21372211).

Scheme 1

One-pot two-step synthesis of spirocyclic oxindole 3ba.

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6

7 Scheme 2 Proposed mechanism for the formation of spirocyclic oxindoles 3.

Conflicts of interest

8

There are no conflicts to declare.

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