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Article

Double Spirocyclization of Arylidene-Δ2-Pyrrolin-4-Ones with 3-Isothiocyanato Oxindoles

by
Sebastijan Ričko
,
Žan Testen
,
Luka Ciber
,
Franc Požgan
,
Bogdan Štefane
,
Helena Brodnik
,
Jurij Svete
and
Uroš Grošelj
*
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia
*
Author to whom correspondence should be addressed.
Catalysts 2020, 10(10), 1211; https://doi.org/10.3390/catal10101211
Submission received: 25 September 2020 / Revised: 13 October 2020 / Accepted: 14 October 2020 / Published: 19 October 2020
(This article belongs to the Special Issue Organocatalysis: Advances, Opportunity, and Challenges)
Browse Figures
Review Reports Versions Notes

Abstract

:
Arylidene-Δ2-pyrrolin-4-ones undergo organocatalyzed double spirocyclization with 3-isothiocianato oxindoles in a domino 1,4/1,2-addition sequence. The products contain three contiguous stereocenters (ee up to 98%, dr up to 99:1, 12 examples). The absolute configuration of the major diastereomer was determined by single crystal X-ray analysis. Along with heterocyclic Michael acceptors based on oxazolone, isoxazolone, thiazolidinone, pyrazolone, and pyrimidinedione, the reported results display the applicability of unsaturated Δ2-pyrrolin-4-ones (pyrrolones) for the organocatalyzed construction of 3D-rich pyrrolone-containing heterocycles.

Graphical Abstract

1. Introduction

Spirooxindoles, containing various spiro rings attached at the C-3 position of the oxindole framework, represent a privileged core scaffold frequently encountered in natural and synthetic products exhibiting many different biological activities [1,2,3,4], as shown in Figure 1 [5,6,7,8,9]. Conformational rigidity of spirooxindoles provides an excellent strategy to enforce the desired conformation for a specific and strong ligand-protein binding [10].
Development of new catalytic methods for stereoselective construction of diverse spirooxindole frameworks, possessing both a variable pharmacophore and functional groups that enable follow-up transformations (i.e., the generation of compound libraries for the evaluation of their biological activities), represents an important ongoing challenge. In this context, organocatalysis has emerged as a powerful synthetic tool for the preparation of complex molecular architectures from simple starting materials, especially due to its operational simplicity, easily available catalysts, and benign reaction conditions [11,12,13,14,15,16,17,18,19,20,21]. 3-Isothiocyanato oxindoles, possessing both the nucleophilic and the electrophilic reaction site, represent a convenient building block for the cascade construction of diverse heterocyclic systems [22,23,24,25]. These transformations can be conducted under mild organocatalytic conditions in a highly stereoselective manner. Thus, various mono- and bis-spiroheterocycles and their fused analogues have been constructed featuring thioimidazolidinone-spirooxindoles [26,27,28,29,30], fused-thioimidazolidinone-spirooxindoles [31], thiopyrrolidinone-spirooxindoles [32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52], fused-thiopyrrolidinone-spirooxindoles [53,54,55,56], thiooxazolidinone-spirooxindoles [57,58,59], and thio-1,2,4-triazolidinone [60].
For the construction of bis-spiroheterocyclic thiopyrrolidinone-spirooxindoles with 3-isothiocyanato oxindoles, arylidene or (functionalized) alkylidene (hetero)cyclic Michael acceptors have been applied. Thereof, bicyclic systems are prevalent (i.e., indole, tetralone, and indanone-derived Michael acceptors) [33,35,37,38,40,41,46,47,52]. Among monocyclic heterocycles, Michael acceptors based on oxazolone [49], isoxazolone [45], thiazolidinone [36], pyrazolone [45,51], and pyrimidinedione (barbituric acid) [39] have been applied, with no reports on the application of pyrrolone-derived 1,4-acceptors (Scheme 1). The pyrrolone (Δ2-pyrrolin-4-one) core is an interesting motif prominent in several natural products (Brevianamide A [61]), bioactive molecules (modulators of opioid receptors [62], antimalarials [63,64], HIV-1 protease inhibitors [65]), and phytopharmaceuticals (herbicides [66]).
In continuation of our research on the implementation of pyrrolone derivatives in asymmetric organocatalyzed transformations [67,68,69,70], we herein report a successful application of the arylidene-Δ2-pyrrolin-4-ones [71] 1 for the enantioselective construction of oxindole-thiopyrolidinone-Δ2-pyrrolin-4-one bis-spiroheterocycles 3 (Scheme 1).

2. Results and Discussion

The DABCO-catalyzed reaction between methyl (E)-5-benzylidene-1,2-dimethyl-4-oxo-4,5-dihydro-1H-pyrrole-3-carboxylate (1a) and 3-isothiocyanato-1-methylindolin-2-one (2a) in THF yielded the corresponding racemic oxindole-thiopyrrolidineone-Δ2-pyrrolin-4-one rac-3a. The subsequent screening of the chiral noncovalent bifunctional organocatalysts I-VII based on camphor, cyclohexane-1,2-diamine, and quinuclidine in toluene at 25 °C is presented in Scheme 2. Several cyclohexane-1,2-diamine- and quinuclidine-based catalysts (VIb, VIIIb, IXb, Xb, XIb) containing either the thiourea or the squaramide H-bond donor and 3,5-bis(trifluoromethyl)phenyl group are compatible with the model reaction 1a + 2a→3a in both yields and stereoselectivity. Among the screened catalysts, the best results along with the cleanest reaction profile were obtained with the catalyst IXb (dr = 95:5, ee = 79%, 60% yield).
With the optimal catalyst IXb in hand, solvent optimization for the reaction 1a + 2a→3a was performed (Table 1). Compared to toluene (Entry 1, 79% ee), the enantioselectivity decreased significantly in dichloromethane, acetonitrile, and methanol (Entries 6, 10, 11; up to 52% ee), while in ethereal solvents (Entries 2, 5, 9) and acetone (Entry 8), the enantioselectivity improved (82–87% ee). A drop of diastereoselectivity was observed in diethyl ether, acetonitrile, and methanol (Entries 3, 10, 11). In terms of yield, the conversion was lower in the majority of the tested solvents (Entries 2–6, 8–11). Trifluorotoluene (Entry 7) gave the cleanest reaction profile with practically unchanged diastereoselectivity, alongside the highest yield and enantioselectivity (dr = 93:7, ee = 87%, 67% yield).
Having established the optimal reaction conditions (catalyst IXb, trifluorotoluene), the scope of the studied transformation was evaluated. For that purpose, several Δ2-pyrrolin-4-ones 1 [71,72] and two 3-isothiocyanato oxindoles 2 [30,53,59] were applied (Figure 2). The results of the investigated scope are presented in Scheme 3. With the N-methyl-substituted Δ2-pyrrolin-4-ones 1a–g, the effect of electron-donating and electron-withdrawing substituents on the phenyl ring of the arylidene moiety, including tiophen-2-yl moiety, did not establish a clear trend; the products were isolated with good to excellent enantioselectivities (80–98% ee), diastereoselectivity above 75:25, and low to moderate yields (18–67%). Despite our best efforts, stereoisomers of the products rac-3m–p, derived from pyrrolones 1h–k and unsubstituted 3-isothiocyanato oxindole 2a, could not be separated on chiral HPLC columns (see the Supplementary Materials). The products 3f–j, derived from 5-methyl substituted 3-isothiocyanato oxindole 2b, compared with the products 3a–e, derived from unsubstituted 3-isothiocyanato oxindole 2a, were generally formed in slightly higher enantioselectivities though lower yields at longer reaction times.
The absolute configuration (3R,3′S,4′R) of the major stereoisomer of the product 3b was determined by single crystal X-ray analysis (Figure 3) (see the Supplementary Materials). Consequently, the same absolute configuration (3R,3′S,4′R) was assigned to all the major diastereomers of products 3a–j. The reaction of 3-isothiocyanato oxindoles 2a and 2b with N-unsubstituted pyrrolones 1l and 1m yielded the corresponding products 3k and 3l in low yields (7 and 14%), and low to moderate enantioselectivities (21 and 57% ee), respectively. Based on previous observations, where enantiomeric products were obtained in the reaction of (E)- and (Z)-pyrrolones 1 with 2-mercaptoacetaldehyde [71], an enantiomeric relationship of (3S,3′R,4′S) was tentatively assigned to products 3k and 3l (Scheme 3).
The follow-up methylation of compound 3a with iodomethane in the presence of K2CO3 in acetone gave the S-methylated product 4 (Scheme 4).
According to the Grayson [72,73] proposal of stereochemistry origin in squaramide-catalyzed asymmetric Michael addition reactions and the observed absolute configuration revealed by X-ray analysis of the major diastereomer of compound 3b (cf. Figure 3), a plausible transition state (TS) leading to the product (as exemplified for the formation of product 3a) can be postulated (Scheme 5). The protonated catalyst activates and coordinates the pyrrolone electrophile via the protonated quinuclidine moiety, while the squaramide functionality simultaneously orients and activates the nucleophile for the attack. The Si face of the nucleophile attacks the Re face of the electrophile, which is followed by the spiro-cyclisation yielding product 3a (Scheme 5).

3. Materials and Methods

3.1. Materials and Methods, Syntheses, and Characterization

Solvents for chromatography and extractions were of technical grade. They were distilled prior to use. Technical grade anhydrous Na2SO4 was used for drying of extracts. Melting points were determined on a Kofler micro hot stage and an SRS OptiMelt MPA100-Automated Melting Point System (Stanford Research Systems, Sunnyvale, CA, USA). The NMR spectra were obtained on a Bruker UltraShield 500 plus (Bruker, Billerica, MA, USA) at 500 MHz for 1H and 126 MHz for a 13C nucleus, using DMSO-d6 and CDCl3 with TMS as the internal standard, as solvents. Mass spectra were recorded on an Agilent 6224 Accurate Mass TOF LC/MS (Agilent Technologies, Santa Clara, CA, USA), and IR spectra on a Perkin-Elmer Spectrum BX FTIR spectrophotometer (PerkinElmer, Waltham, MA, USA). Column chromatography (CC) was performed on silica gel (Silica gel 60, particle size: 0.035–0.070 mm (Sigma-Aldrich, St. Louis, MO, USA)). HPLC analyses were performed on an Agilent 1260 Infinity LC (Agilent Technologies, Santa Clara, CA, USA) using CHIRALPAK IA-3 (0.46 cm ø × 25 cm), CHIRALPAK AD-H (0.46 cm ø × 250 mm), CHIRALCEL AS-H (0.46 cm ø × 250 mm), and CHIRALCEL OD-H (0.46 cm ø × 250 mm) as chiral columns (CHIRAL TECHNOLOGIES, INC., West Chester, PA, USA). All the commercially available chemicals used were purchased from Sigma-Aldrich (St. Louis, MO, USA).
Methyl 5-arylidene-2-methyl-4-oxo-4,5-dihydro-1H-pyrrole-3-carboxylates 1 [71] and 3-isothiocyanatooxindoles 2a and 2b [30,53,59] were prepared following the literature procedures.
Organocatalysts Ia [70], II [69], IIIa [70], IV [70], Vb [74], VIa [75], VIb [76], VIIa [77], VIIb [76], IXa [78], IXb [79], IXc [80], Xb [81], XIa [19], and XIb [78] were prepared following the literature procedures; organocatalysts VIIIb and XII were purchased from Sigma-Aldrich.

3.2. Synthesis of (E)-Methyl 5-Arylidene-1,2-Dimethyl-4-oxo-4,5-Dihydro-1H-Pyrrole-3-Carboxylate-General Procedure 1 (GP1)

To a solution of methyl (Z)-2-(2-chloroacetyl)-3-(methylamino)but-2-enoate (E) [71] (1 equivalent) in anhydrous EtOH at room temperature, KOH (1.05 equivalent, ω = 0.85) was added and the resulting reaction mixture was heated to 75 °C. After the disappearance of the starting material (ca. 45 min), according to the TLC analysis (mobile phase: EtOAc/MeOH = 4:1) (Figure S1), the mixture was cooled to room temperature. KHSO4 (0.5 equivalent) was added, followed by the addition of H2O (5 mL), and the mixture was stirred for 10 min at room temperature, followed by the addition of an aldehyde (1 equivalent). The mixture was heated to 75 °C and stirred until the disappearance of the Δ2-pyrrolin-4-one intermediate A (ca. 30 min), according to the TLC analysis (mobile phase: EtOAc/MeOH = 4:1) (Figure S1). Afterwards, the solution was cooled to room temperature, followed by the slow addition of ice-cold water (ca. 100 mL) until the formation of the precipitate. The precipitate was collected by filtration, washed with ice-cold water, and dried under a high vacuum at 60 °C. Unless noted otherwise, the crude product was purified by recrystallization from MeOH/H2O and dried under a high vacuum at 60 °C, which afforded the product 1 (compounds 1c, 1f, 1g, 1i) as a brightly colored solid. Other 5-arylidene-2-methyl-4-oxo-4,5-dihydro-1H-pyrrole-3-carboxylates were prepared following the literature procedures [71].

3.3. Organocatalyzed Bis-Spiroheterocyclization-Preparation of Racemic Mixtures-General Procedure 2 (GP2)

To a mixture of arylidene-Δ2-pyrrolin-4-one 1 (0.1 mmol), 3-isothiocyanato oxindole 2 (0.13 mmol), and 1,4-diazabicyclo[2.2.2]octane (DABCO) (0.01 mmol, 1.12 mg) under argon, anhydrous THF (1 mL) was added and the resulting reaction mixture was stirred at 25 °C for 24 h. Volatile components were evaporated in vacuo and the residue was purified by column chromatography (Silica gel 60, mobile phase: EtOAc/petroleum ether = 2:1). Fractions containing the pure racemic product rac-3 were combined and volatile components were evaporated in vacuo followed by HPLC analysis on chiral columns. Products rac-3 (compounds rac-3k-n), that could not be separated on chiral columns, were fully characterized.

3.4. Organocatalyzed Stereoselective Bis-Spiroheterocyclization-General Procedure 3 (GP3)

To a mixture, arylidene-Δ2-pyrrolin-4-one 1 (0.1 mmol), 3-isothiocyanato oxindole 2 (0.13 mmol), and organocatalyst I-XII (10 mol%) under argon, anhydrous solvent (1 mL) was added and the resulting reaction mixture was stirred at 25 °C for 24–72 h.
(i) For catalyst and solvent screening (model reaction 1a + 2a→3a), volatile components were evaporated in vacuo and the residue was purified by flash column chromatography to remove the catalyst (Silica gel 60, mobile phase: EtOAc/petroleum ether = 2:1). Fractions containing the product 3a were combined and volatile components were evaporated in vacuo followed by determination of the enantiomeric excess and diastereomeric ratio by HPLC analysis.
(ii) For the reaction scope synthesis (reactions 1 + 2→3; compounds 3a–l), volatile components were evaporated in vacuo and the residue was purified by column chromatography (Silica gel 60, mobile phase: EtOAc/petroleum ether = 2:1). Fractions containing pure product 3 were combined and volatile components were evaporated in vacuo, followed by determination of the enantiomeric excess by HPLC analysis, determination of the diastereomeric ratio by 1H-NMR, and full characterization.

4. Conclusions

We have shown that Michael acceptors based on Δ2-pyrrolin-4-ones (pyrrolones), which are easily prepared from bulk chemicals [71], undergo stereoselective organocatalyzed double spiro-cyclization with 3-isothiocianato oxindoles. A library of 12 products containing three contiguous stereocenters (ee up to 98%, dr up to 99:1) has been synthesized and a follow-up transformation demonstrated. This research offers a new entry for the construction of 3D-rich pyrrolone-containing heterocycles.

Supplementary Materials

The following are available online at https://www.mdpi.com/2073-4344/10/10/1211/s1, Synthesis and Characterization Data for Compounds 1 and 3; HPLC data; Copies of 1H- and 13C-NMR spectra; Structure Determination by NMR-NOESY spectra (for compounds 1); Copies of HRMS reports of Compounds 1 and 3; Structure Determination by X-ray Diffraction Analysis, Figure S6: Ortep drawing of compound 3b.

Author Contributions

For Conceptualization, U.G., S.R., J.S., F.P., and B.Š.; methodology, U.G. and S.R.; software, U.G., S.R., L.C., J.S., F.P., and B.Š.; validation, U.G., S.R., J.S., F.P., and B.Š.; formal analysis, U.G., Ž.T., H.B., and S.R.; investigation, S.R., Ž.T., L.C., and U.G.; resources, U.G., S.R. and J.S.; data curation, U.G., Ž.T., L.C., J.S., S.R., F.P., H.B., and B.Š.; writing—original draft preparation, U.G., S.R., J.S., F.P., and B.Š.; writing—review and editing, U.G., J.S., S.R., L.C., F.P., and B.Š.; visualization, U.G., B.Š., and J.S.; supervision, U.G.; project administration, U.G. and J.S.; funding acquisition, J.S., U.G., F.P., and B.Š. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Slovenian Research Agency through grants P1-0179 and P1-0175.

Acknowledgments

We thank EN-FIST Centre of Excellence, Trg Osvobodilne fronte 13, 1000 Ljubljana, Slovenia, for using BX FTIR spectrophotometer and Agilent 1260 Infinity HPLC system.

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 10 01211 g001 550
Figure 1. Selected biologically active compounds possessing a spirooxindole scaffold.
Figure 1. Selected biologically active compounds possessing a spirooxindole scaffold.
Catalysts 10 01211 g001
Catalysts 10 01211 sch001 550
Scheme 1. Bis-spiroheterocyclic oxindoles containing oxazolone, thiazolidinone, pyrazolone, pyrimidinedione, and pyrrolone structural motifs.
Scheme 1. Bis-spiroheterocyclic oxindoles containing oxazolone, thiazolidinone, pyrazolone, pyrimidinedione, and pyrrolone structural motifs.
Catalysts 10 01211 sch001
Catalysts 10 01211 sch002 550
Scheme 2. Evaluation of organocatalysts I-XII in a model reaction 1a + 2a→3a.
Scheme 2. Evaluation of organocatalysts I-XII in a model reaction 1a + 2a→3a.
Catalysts 10 01211 sch002
Catalysts 10 01211 g002 550
Figure 2. Selected 5-arylidene-2-methyl-4-oxo-4,5-dihydro-1H-pyrrole-3-carboxylates 1 and 3-isothiocyanato oxindoles 2; color red—novel reported pyrrolones 1.
Figure 2. Selected 5-arylidene-2-methyl-4-oxo-4,5-dihydro-1H-pyrrole-3-carboxylates 1 and 3-isothiocyanato oxindoles 2; color red—novel reported pyrrolones 1.
Catalysts 10 01211 g002
Catalysts 10 01211 sch003 550
Scheme 3. Synthesized bis-spiroheterocycles 3.
Scheme 3. Synthesized bis-spiroheterocycles 3.
Catalysts 10 01211 sch003
Catalysts 10 01211 g003 550
Figure 3. Single crystal X-ray structure depicting product 3b. Thermal ellipsoids are shown at 50% probability.
Figure 3. Single crystal X-ray structure depicting product 3b. Thermal ellipsoids are shown at 50% probability.
Catalysts 10 01211 g003
Catalysts 10 01211 sch004 550
Scheme 4. Follow-up methylation of compound 3a.
Scheme 4. Follow-up methylation of compound 3a.
Catalysts 10 01211 sch004
Catalysts 10 01211 sch005 550
Scheme 5. Postulated transition state leading to the product 3a.
Scheme 5. Postulated transition state leading to the product 3a.
Catalysts 10 01211 sch005
Table
Table 1. Evaluation of organocatalyst IXb in bis-spiroheterocyclization of 5-arylidene-Δ2-pyrrolin-4-one 1a with 3-isothiocyanatooxindole 2a. a
Table 1. Evaluation of organocatalyst IXb in bis-spiroheterocyclization of 5-arylidene-Δ2-pyrrolin-4-one 1a with 3-isothiocyanatooxindole 2a. a
Catalysts 10 01211 i001
SolventYield (%)dree (%)
1toluene6095:579
21,4-dioxane4693:783
3Et2O3580:2075
41,2-dimethoxyethane4995:578
5THF5594:682
6CH2Cl26193:76
7PhCF36793:787
8acetone4494:687
9t-butyl methyl ketone4195:587
10MeCN3079:2152
11MeOH3486:1436
a 5-Arylidene-Δ2-pyrrolin-4-one 1a (0.1 mmol), 3-isothiocyanato oxindole 2a (0.13 mmol), catalyst IXb (10 mol%), solvent (1 mL), 25 °C, 24 h; ee and dr determined by HPLC after flash column chromatography.
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Ričko, S.; Testen, Ž.; Ciber, L.; Požgan, F.; Štefane, B.; Brodnik, H.; Svete, J.; Grošelj, U. Double Spirocyclization of Arylidene-Δ2-Pyrrolin-4-Ones with 3-Isothiocyanato Oxindoles. Catalysts 2020, 10, 1211. https://doi.org/10.3390/catal10101211

AMA Style

Ričko S, Testen Ž, Ciber L, Požgan F, Štefane B, Brodnik H, Svete J, Grošelj U. Double Spirocyclization of Arylidene-Δ2-Pyrrolin-4-Ones with 3-Isothiocyanato Oxindoles. Catalysts. 2020; 10(10):1211. https://doi.org/10.3390/catal10101211

Chicago/Turabian Style

Ričko, Sebastijan, Žan Testen, Luka Ciber, Franc Požgan, Bogdan Štefane, Helena Brodnik, Jurij Svete, and Uroš Grošelj. 2020. "Double Spirocyclization of Arylidene-Δ2-Pyrrolin-4-Ones with 3-Isothiocyanato Oxindoles" Catalysts 10, no. 10: 1211. https://doi.org/10.3390/catal10101211

APA Style

Ričko, S., Testen, Ž., Ciber, L., Požgan, F., Štefane, B., Brodnik, H., Svete, J., & Grošelj, U. (2020). Double Spirocyclization of Arylidene-Δ2-Pyrrolin-4-Ones with 3-Isothiocyanato Oxindoles. Catalysts, 10(10), 1211. https://doi.org/10.3390/catal10101211

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