Article pubs.acs.org/joc
Cite This: J. Org. Chem. 2018, 83, 2660−2675
Stereoselective Synthesis of 3,3-Disubstituted Oxindoles and Spirooxindoles via Allylic Alkylation of Morita−Baylis−Hillman Carbonates of Isatins with Cyclic Sulfamidate Imines Catalyzed by DABCO Sanjeeva K. Arupula, Soumitra Guin, Anubha Yadav, Shaikh M. Mobin, and Sampak Samanta* Discipline of Chemistry, Indian Institute of Technology Indore, Simrol, Indore-453552, Madhya Pradesh, India S Supporting Information *
ABSTRACT: An efficient, organocatalytic, and ecofriendly method has been developed for the quick construction of a wide array of 3,3-disubstituted oxindoles in good to excellent yields and diastereomeric ratio (up to ≤96:4) with excellent functional group tolerance via an allylic alkylation reaction of cyclic sulfamidate imines with a number of MBH carbonates of isatins in 2-MeTHF as an environmentally benign solvent at room temperature using 5 mol % of DABCO. Furthermore, a metal-free-based one-shot synthesis of a medicinally promising polycyclic spirooxindole with an all-carbon spirocenter has been achieved with outstanding dr value (up to ≤99:1).
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INTRODUCTION The design and efficient construction of N-containing heterocycles bearing an oxindole framework particularly 3,3disubstituted oxindole and spirooxindole are of great challenge for synthetic organic and medicinal chemists.1 These privileged heterocycles have been well recognized and identified as key structural units in many bioactive natural and non-natural products as well as pharmaceuticals.1,2 They exhibit diverse biological activities namely potential antidepressant,3 antiviral,4 anticancer,5 anti-HIV,6 antidengue,7 antimalarial,8 5-HT7 receptor antagonist,9 etc. (Figure 1). Due to their biological importance, efforts have been made for the synthesis of both racemic and enantioenriched versions of 3,3-disubstituted oxindoles by relying on several modern techniques.1,2,10−14 These include nucleophilic addition to isatins1c,2b/isatinimines,11 oxidative C−H functionalization of N-arylacrylamides,12 nucleophilic substitution/Michael reaction involving 3-monosubstituted oxindoles as nucleophiles,13 the decarboxylative addition of β-ketoacids to isatylidene malononitriles14a/ 3-haloisatins14b promoted by several transition-metal catalysts and organocatalysts. Alternatively, an efficient access to C3quaternary 2-oxindole frameworks was also achieved via an allylic substitution15 of MBH carbonates of isatins with several C/N/S-nucleophiles such as α,α-dicyanoolefins,15a γ-butenolide, 15b nitroalkanes, 15c 3,5-dimethyl-4-nitroisoxazole, 15d CbzNHOTBS,15e and alkylthiols15f in the presence of Lewisbases as developed independently by Chen and other groups (Scheme 1a). Despite substantial progress, there is no report of allylic alkylation of isatin-derived MBH carbonate involving widely recognized cyclic sulfamidate imines as useful synthons,16 even though the above combination may offer a novel class of 3,3-disubstituted oxindoles with a quaternary © 2018 American Chemical Society
stereogeneic center at the C3 position. On the other hand, our group has shown that cyclic sulfamidate imines could be used as efficient carbon nucleophiles,17 while reacting with several electrophiles, namely MBH acetates of nitroolefins/ketones/ acrylate, aldehydes, conjugated aldehydes/ketones, etc. Along these lines, we further disclose herein a quick and efficient stereoselective synthesis of pharmacologically interesting 3,3disubstituted oxindoles by involving cyclic sulfamidate imines as useful nucleophiles and several MBH carbonates of isatins in 2MeTHF as green solvent using 5 mol % of DABCO as a Lewis base organocatalyst (Scheme 1b).
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RESULTS AND DISCUSSION To optimize the reaction conditions, the initial reaction between five-membered cyclic sulfamidate imine 1a and MBH carbonate derived from N-benzylisatin 2a was performed in CH2Cl2 at room temperature using DABCO (5.0 mol %) as a nucleophile catalyst. After 5 min, the desired 3,3-disubstituted oxindole 3aa as a major isomer was obtained in 70% yield (Table 1, entry 1) with 92:8 diastereoselectivity. To know the effects of solvents, different organic solvents, namely THF, 2MeTHF (green solvent), toluene, MeCN, DMF, and H2O, were screened for this allylic alkylation reaction. Among them, 2-MeTHF (entry 4) showed excellent results in terms of yield (87%) and diasteromeric ratio (96:4) as compared to other solvents tested for this substitution reaction. It should be noted that other Lewis base catalysts such as DMAP, Et3N, DBU, DIPEA, and PPh3 were shown to be ineffective for this conversion (entries 8−12). Received: December 7, 2017 Published: February 7, 2018 2660
DOI: 10.1021/acs.joc.7b03090 J. Org. Chem. 2018, 83, 2660−2675
Article
The Journal of Organic Chemistry
Figure 1. Examples of biologically significant 3,3-disubstituted oxindoles and spirooxindoles.
Scheme 1. Allylic Alkylation of MBH Carbonate of Isatins Using Several Nucleophiles
% of DABCO to produce high yields (84−87%) of the corresponding major isomers (3aa−ae, Table 2) possessing an all-carbon quaternary stereogenic center in similar ranges of dr values (93:7 to 96:4). Expectedly, the incorporation of halogen atoms (F, Cl, and Br) on the aryl rings of cyclic imines (1d−f) resulted in slightly lower yields (77−83%, 3de−fc) as compared to electron-donating ones (Me and OMe, 86−90%, 3ba−ce) under identical reaction conditions. Besides, 4heteroaryl-substituted cyclic imine 1g also actively participated in the present C−C bond-forming reaction with 2a and offered 76% yield of 3ga with excellent diastereoselectivity (97:3 dr). Similarly, attaching electron poor (Cl, F, NO2) substituents on the aryl-rings of MBH carbonates (2f−h) led to 2−8% lesser yields of major isomers as compared to donating ones (80− 86% of 3af−ah vs 88% of 3ai) after 9 min, while reacting with 1a. The relative stereochemistry of all the compounds 3aa−ai was confirmed by single-crystal X-ray diffraction data of 3ca and 3be as two examples, indicating that the C−O bond of the cyclic imine and the amide bond of the 2-oxindole moiety are anti to each other as shown in Figure 2. Inspired by the results obtained with five-membered cyclic sulfamidate imines, we then turned our attention to examine
In view of the above reaction results and previously disclosed reports, we proposed a plausible mechanism for the formation of 3aa as shown in Scheme 2. Initially, Lewis base DABCO acts as a nucleophilic trigger which attacks the β-position of acrylate 2a in a SN2′ manner to form reactive allylammonium intermediate 2a′. Next, the carbanion intermediate 1a′ is generated through a deprotonation of 1a by in situ-generated tert-butoxide anion. The former undergoes SN2′ reaction with 2a′ to give allylic adduct 3aa. The observed stereochemical outcome may be explained from the TS-I model in the attack of 1a′ to 2a′ which is stabilized by π−π interaction between the phenyl and aryl ring of oxindole along with possible electrostatic interaction between the oxygen lone pair of 1a′ and the positive charge on the N atom of 2a′, leading to 3aa with high diastereoselectivity. By employing the optimal reaction conditions, the scope and generality of this allylic substitution reaction was subsequently explored by taking a wide range of 4-aryl/heteroaryl-substituted cyclic sulfamidate imines (1a−g) with several MBH carbonates of isatins (2a−i). As illustrated in Table 2, cyclic imine 1a underwent rapid and spotless reaction with a number of Nprotected isatin-derived MBH carbonates (2a−e) using 5 mol 2661
DOI: 10.1021/acs.joc.7b03090 J. Org. Chem. 2018, 83, 2660−2675
Article
The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditionsa
entry
catalyst
solvent
time (min)
yield (%)b
drc 3aa:4aa
1 2 3 4 5 6 7 8 9 10 11 12
DABCO DABCO DABCO DABCO DABCO DABCO DABCO DMAP NEt3 PPh3 DIPEA DBU
CH2Cl2 THF toluene 2-MeTHF CH3CN DMF H2O 2-MeTHF 2-MeTHF 2-MeTHF 2-MeTHF 2-MeTHF
5 5 5 5 5 20 60 30 30 30 30 30
70 84 73 87 72 65 NRd
