Dieckmann Cyclization Reaction

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Organocatalytic Asymmetric Michael/Dieckmann Cyclization Reaction of Alkynones To Construct Spirocyclopentene Oxindoles Jiawen Lang, Yi Li, Tengfei Kang, Xiaoming Feng, and Xiaohua Liu* Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China

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S Supporting Information *

ABSTRACT: A highly enantioselective conjugate addition/ Dieckmann cyclization of 3-carboxymethyl substituted oxindoles with electron-deficient internal alkynes was achieved under the catalysis of a chiral guanidine catalyst and NaH. This protocol provides access to a wide range of synthetically useful optically active spirocyclopentenone oxindoles and their derivatives under mild reaction conditions.

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Scheme 1. Representative Enantioselective Reactions for Accessing Cyclopentene-Fused Spirooxindoles

pirooxindole scaffolds are widely present in natural alkaloids and biologically active molecules.1 Numerous creative catalytic asymmetric reactions have been developed to incorporate different cyclic motif into oxindole cores in recent several years.2 Among them, enantioselective synthesis of cyclopentene oxindoles is a formidable synthetic task. One direct approach is the asymmetric [3 + 2] cycloaddition of methyleneindolinones promoted by chiral phosphine organocatalysts. In 2010, the Marinetti group reported stereoselective [3 + 2] cycloaddition with allenoates to give γ-adduct spirocyclopentene oxindoles (Scheme 1a).3 Using Morita− Baylis−Hillman (MBH) carbonates as the C3-synthons, Barbas and Lu realized α- and γ-selective [3 + 2] cycloadditions, independently (Scheme 1b).4 Alternatively, the Chen group designed β-ICD O-MOM ether-catalyzed [3 + 2] annulation of oxindole-based MBH carbonates with propargyl sulfones or activated olefins for this purpose.5 Besides, the Wang group synthesized cyclopentene-fused oxindoles from 3proynyl oxindoles and α,β-unsaturated aldehydes through the merger of iminium/enamine-palladium synergistic catalysis (Scheme 1c).6 The Correia group utilized Heck−Matsuda desymmetrization of prochiral cyclopentene oxindoles to access chiral spirooxindole derivatives (Scheme 1d).7 Apart from these studies, the titled nonstereoselective cascade reaction was disclosed for the synthesis of cyclopentenonefused oxindoles in the presence of excessive amount of Cs2CO3.8 It is of interest to develop an enantioselective approach to construct this type of product (Scheme 1e) in view of further elaboration into other complicate scaffolds and drug discovery and development. We have been studying a straightforward enantioselective synthesis of five-membered heterocyclic spirooxindoles through double Michael additions between 3-substituted oxindoles and alkynones.9 The bifunctional chiral guanidine catalysts,9b,10 which have proven particularly effective for the activation of both electrophiles and Michael acceptors, are well suited to a variety of 3-substituted oxindoles and others. We thus wondered whether this approach might be portable to © XXXX American Chemical Society

Michael/Dieckmann cyclization11 between 3-carboxymethyl substituted oxindoles and alkynones. Nevertheless, this asymmetric catalytic cascade reaction is more challenging. Internal alkynones are relative less reactive Michael acceptors,12 and a strong achiral base used for Dieckmann condensation might bring dramatic nonselective background Received: July 19, 2019

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DOI: 10.1021/acs.orglett.9b02519 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters reaction.8 We now describe an asymmetric access to spirocyclopentenone oxindoles catalyzed by a combination of chiral guanidine and NaH (Scheme 1e). Good yields and excellent enantioselectivities are available with a low amount of chiral organocatalyst under mild reaction conditions. In accord with our previous studies,9b we presumed that exposure of 3-carboxymethyl substituted oxindole 1a to chiral guanidine catalysts G would generate activated electrophilic species that can enantioselectively yield at least the Michael adduct 5aa of alkynone 2a. Nevertheless, neither conjugate addition product 5aa nor cascade reaction product 3aa was detected in the initial experiment with G-1 in CH2Cl2 at 30 °C (Table 1, entry 1). It was envisioned that additional bases

88% ee, along with the Michael addition product (E)-5aa in 15% yield with 93% ee (entry 2). When NaH was chosen as the base additive, a slightly higher ee value could be achieved (entry 3). Inspired by these results, other chiral guanidine catalysts were evaluated in combination with NaH (entries 4− 7). We found that the amino acid backbone has an obvious influence on the enantioselectivity, and L-pipecolic acid derived ones (G-1−G-3) gave higher ee values than L-proline-based G4 and L-ramipril-based G-5 (entries 3−5 vs entries 6 and 7). Increasing the steric hindrance of the para-substituent on the phenylsulfonyl moiety of the guanidine resulted in slightly higher enantioselectivity, and the guanidine G-2 yielded the best results (entries 3−5). Next, the addition of 3 Å MS promoted the yield to 83%, and the byproduct (E)-5aa was decreased (entry 8). Subsequent solvent screening (entries 8− 11) indicated that the mixture of Et2O and EtOAc could give an improved yield of 93% with a balanced ee value along with byproduct (E)-5aa in trace yield (entry 11). Lowering the temperature to −10 °C led to a slight improvement of yield and enantioselectivity (entry 12). Furthermore, the substrate 4a with bulky isopropyl ester group resulted in the formation of the desired product 3aa in 98% yield with 98% ee value (entry 13). Finally, excellent results could also be obtained within 2 h, even when the loading of guanidine G-2 was decreased to 2 mol % (entry 14). Next, the generality of the protocol for different alkynones was explored (Table 2). Generally, a diverse array of benzoyl substituents bearing electron-donating or electron-withdrawing groups was found to be tolerable in this reaction, and the corresponding products (3aa−3al) were afforded with high yields (91−99%) and excellent ee values (93−>99% ee). It is worth mentioning that 4-chloro-subsituted substrate 2i and 4bromo-subsituted 2j, which are electron-deficient and more likely to undergo the nucleophilic addition reaction, could get good results even by decreasing the amount of guanidine G-2 to 1 mol % (entries 9 and 10). But when 2-bromophenyl substituted 2d and 1-naphthyl substituted 2m were used, the amount of guanidine was increased a little in order to suppress the inorganic base-raised nonselective competitive pathway (3ad and 3am). We proposed that the steric hindrance lies between R1 and the chiral guanidine catalyst G-2; the oxindole 4 as well will weaken the enantioselective process. To our delight, heteroaromatic alkynones were also suitable substrates for this reaction, giving the corresponding products 3an−3ap with excellent results (entries 14−16). Phenylethyl substituted alkynone 2q with a long carbon chain delivered the corresponding product 3aq in 80% yield with 92% ee value (entry 17). Furthermore, both cyclic and linear aliphatic alkynones proceeded well to afford the spirooxindoles 3ar and 3as in 84% yield with 98% ee and 81% yield with 98% ee, respectively (entries 18 and 19). In these two cases, 5 mol % of guanidine was used to reduce the amount of Michael adducts. Additionally, electron-withdrawing or -donating substituents, heteroaromatic and aliphatic groups (R2) at the alkynyl terminus on alkynones were well amenable to the cascade reaction, delivering enantiomeric enriched products (3at−3ay) with good to high yields and enantioselectivities (entries 20− 25). The absolute configuration of 3aj was determined to be (R) by X-ray crystallographic analysis.13 Subsequently, variations of substituted 3-carboxymethyl oxindoles 4 were studied in this reaction (Table 3). We found that electron-donating substituents (R3) on the phenyl backbone of oxindoles tolerated well under the standard

Table 1. Optimization of the Reaction Conditionsa

yield (%)b

ee (%)c

entry

G

base

solvent

3aa

5aa

3aa

5aa

1 2 3 4 5 6 7 8d 9d 10d 11d,e 12d,e,f 13d,e,f,g 14h

G-1 G-1 G-1 G-2 G-3 G-4 G-5 G-2 G-2 G-2 G-2 G-2 G-2 G-2

− NaOH NaH NaH NaH NaH NaH NaH NaH NaH NaH NaH NaH NaH

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 Et2O EtOAc Et2O/EtOAc Et2O/EtOAc Et2O/EtOAc Et2O/EtOAc

− 67 68 71 70 77 76 83 82 98 93 94 98 97

− 15 12 13 15 8 7 8 7 trace trace trace trace trace

− 88 90 95 92 0 11 94 98 24 95 97 98 97

− 93 94 97 97 5 16 97 97 − − − − −

a

Unless otherwise noted, the reactions were performed with 1a (0.10 mmol), 2a (0.11 mmol), G (10 mol %), base (25 mol %), in solvent (2.0 mL) at 30 °C for 2 h. bIsolated yield. cDetermined by chiral HPLC. d3 Å MS (10 mg) was added. eIn Et2O/EtOAc (7/3 v/v; 2.0 mL). fAt −10 °C. g4a instead of 1a. hThe reaction was performed with 4a (0.20 mmol), 2a (0.22 mmol), G-2 (2 mol %), 3 Å MS (20 mg), NaH (12.5 mol %) in Et2O/EtOAc (7/3 v/v; 4.0 mL) at −10 °C for 2 h.

might promote dienolization of 1a to enhance its nucleophilicity as well as to stabilize the dienoate intermediate, leading to the occurrence of the desired reaction. Indeed, weak bases, such as iPr2NH and K2CO3, remained completely inert; whereas a strong base, such as Cs2CO3, enabled the reaction in high yield but without enantioselectivity (see Supporting Information for details). To our delight, an obviously increased enantioselectivity was obtained when we used a catalytic amount of NaOH as the base additive. The reaction performed well to get the spirooxindole product 3aa in 67% yield with B

DOI: 10.1021/acs.orglett.9b02519 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 2. Substrate Scope of Alkynones for the Reactiona

Table 3. Substrate Scope of Oxindoles for the Reactiona

entry

R1, R2

yield (%)b

ee (%)c

entry

R3

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18f 19f 20 21 22 23 24f 25g

C6H5, Ph 2-MeC6H4, Ph 2-FC6H4, Ph 2-BrC6H4, Ph 3-MeC6H4, Ph 4-MeC6H4, Ph 4-MeOC6H4, Ph 4-FC6H4, Ph 4-ClC6H4, Ph 4-BrC6H4, Ph 4-F3CC6H4, Ph 3,5-Me2C6H3, Ph 1-naphthyl, Ph 3-furanyl, Ph 3-thiophenyl, Ph 3-pyridinyl, Ph phenylethyl, Ph cyclohexyl, Ph n-butyl, Ph Ph, 3-MeOC6H4 Ph, 3-BrC6H4 Ph, 4-MeC6H4 Ph, 2-thiophenyl Ph, cyclopropyl Ph, n-pentyl

97 (3aa) 99 (3ab) 98 (3ac) 97/98d (3ad) 97 (3ae) 94 (3af) 93 (3ag) 96 (3ah) 97/93e (3ai) 98/97e (3aj) 97 (3ak) 91 (3al) 94/95d (3am) 91 (3an) 98 (3ao) 98 (3ap) 80 (3aq) 84 (3ar) 81 (3as) 99 (3at) 94 (3au) 94 (3av) 99 (3aw) 99 (3ax) 70 (3ay)

97 98 95 87/95d 98 99 97 96 99/94e 99/93e (R) 96 >99 86/94d 96 96 96 92 98 98 97 90 98 96 97 88

1 2d 3e 4e 5 6 7f 8 9 10e

5-Me 5-F 5-Br 5-I 6-MeO 6-F 6-Cl 5,7-Me 7-Me 7-F

yield (%)b 97 96 95 93 97 94 98 99 98 96

(3ba) (3ca) (3da) (3ea) (3fa) (3ga) (3ha) (3ia) (3ja) (3ka)

ee (%)c 96 95 94 88 98 95 92 98 98 94

a

Unless otherwise noted, the reactions were performed with 4 (0.20 mmol), 2a (0.22 mmol), G-2 (2 mol %), NaH (12.5 mol %), 3 Å MS (20 mg), in Et2O/EtOAc (7/3 v/v; 4.0 mL) at −10 °C for 2 h. b Isolated yield. cDetermined by chiral HPLC. dG-2 (5 mol %). eG-2 (10 mol %). fG-2 (3 mol %).

Scheme 2. (a) Gram-Scale Experiment, (b) Transformations of Product 3aa, and (c) Control Experiments

a Unless otherwise noted, the reactions were performed with 4a (0.2 mmol), 2 (0.22 mmol), G-2 (2 mol %), NaH (12.5 mol %), 3 Å MS (20 mg), in Et2O/EtOAc (7/3 v/v; 4.0 mL) at −10 °C for 2 h. b Isolated yield. cDetermined by chiral HPLC. dG-2 (4 mol %). eG-2 (1 mol %). fG-2 (5 mol %). gThe reaction was performed at −10 °C for 3 h by using 5 mol % of G-2.

reaction condition, and the desired products could be obtained in excellent yields and ee values (entries 1, 5, 8, and 9). In comparison, oxindole substrates with electron-withdrawing substituents performed the reaction after the chiral catalyst loading increased a little (93−98% yields, 88−95% ee; entries 2−4, 7, and 10). The scalability of this method was demonstrated in the reaction between 3-carboxymethyl substituted oxindole 4a and alkynone 2j at 2 mol % of chiral catalyst, thus providing a gram quantity of the 3,3′-cyclopentenone-fused oxindoles 3aj with excellent yield and enantioselectivity (1.052 g, 96% yield, 95% ee). Next, simple derivatization of the product was conducted. The spirocyclopentenone oxindole 6aa and spirocyclopentene oxindole 7aa via selective reduction of the carbonyl group were obtained without loss of enantioselectivity (Scheme 2b). With the goal of identification of the mechanism, the reaction between oxindole 4a and 1-phenylprop-2-ynone was carried out (Scheme 2c). It was found that guanidine G-2 could promote the Michael reaction smoothly, generating the conjugate adduct (Z)-5a in moderate yield, albeit the enantioselectivity was not satisfied. This selectivity was similar to the chiral guanidines catalyzed (Z)-selective asymmetric 1,4-

addition reaction of 5H-oxazolones with terminal alkynyl carbonyl compounds in Misaki and Sugimura’s work.14 Moreover, following the addition of NaH, isomerization of the (Z)-5a15 occurred to afford the (E)-isomer. However, none of the corresponding Dieckmann cyclization product was detected. In addition, the isolated Michael adduct was (E)5aa,16 which was resubjected into the catalyst system, and no further transformation was observed. These results imply that chiral guanidine catalyst enables the enolization of 3substituted oxindoles directly, and the additional base might stabilize the dienolate intermediate, benefiting the cyclization prior to protonation. Based on the configuration of the product 3aj and control experiments, we propose a possible asymmetric catalytic mode (Scheme 3). The guanidine-sulfonamide G-2 works as a C

DOI: 10.1021/acs.orglett.9b02519 Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

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Scheme 3. Possible Asymmetric Catalytic Modes

Letter

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Xiaoming Feng: 0000-0003-4507-0478 Xiaohua Liu: 0000-0001-9555-0555 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We appreciate the National Natural Science Foundation of China (no. 21625205) and National Program for Support of Top-Notch Young Professionals for financial support.

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bifunctional catalyst, in which the basic guanidine unit promotes the enolization of 3-substituted oxindole 4, contacting the formed nucleophile via hydrogen bonding. The Si-face is shield by the substituents at the guanidine unit. At the same time, the vicinal amide bonds could activate the alkynone 2 via double-hydrogen-bond interaction. Thus, a Reface-selective intermolecular conjugate addition takes place to generate the dienolate intermediate. Inorganic base as NaH, NaOH, or NaOiPr generated in situ will assist the cyclization process efficiently, releasing alcohol to yield the (R)spirocyclopentenone product 3, as well as deprotonation of the guanidium salt to regenerate the chiral bifunctional catalyst at the same time. Otherwise, the minor protonation process performs from the opposite site of the two hindered aryl substituents to afford the thermodynamically stable E-isomer 5. In conclusion, we have successfully established a catalytic system for the asymmetric Michael addition/Dieckmann cyclization reaction of 3-carboxymethyl substituted oxindoles with internal alkynones, under the catalysis of chiral guanidine catalyst and NaH. The methodology has been amply demonstrated through a series of substituted alkynones and oxindoles, which affords a wide range of optically active spirocyclopentene oxindole derivatives under mild conditions. Further application of guanidine catalysts in asymmetric transformations are underway.

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REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02519. Experimental procedures, full spectroscopic data for all new compounds, and copies of 1H, 13C, 19F NMR, and HPLC spectra (PDF) Accession Codes

CCDC 1913922, 1922994, and 1923035 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/ data_request/cif, or by emailing [email protected]. uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. D

DOI: 10.1021/acs.orglett.9b02519 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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Letter

Organic Letters Domino Benzoannulation with Ynones: One-Pot Synthesis of Polyfunctional Naphthalenes and a Total Synthesis of Macarpine. Angew. Chem., Int. Ed. 2018, 57, 16847. (13) CCDC 1913922 (3aj). (14) (a) Misaki, T.; Kawano, K.; Sugimura, T. Highly Z-Selective Asymmetric 1,4-Addition Reaction of 5H-Oxazol-4-ones with Alkynyl Carbonyl Compounds Catalyzed by Chiral Guanidines. J. Am. Chem. Soc. 2011, 133, 5695. (b) Wang, Z.; Chen, Z. L.; Bai, S.; Li, W.; Liu, X. H.; Lin, L. L.; Feng, X. M. Highly Z-Selective Asymmetric Conjugate Addition of Alkynones with Pyrazol-5-ones Promoted by N,N’-Dioxide−Metal Complexes. Angew. Chem., Int. Ed. 2012, 51, 2776. (c) Yang, D. X.; Wang, L. Q.; Kai, M.; Li, D.; Yao, X. J.; Wang, R. Application of a C-C Bond-Forming Conjugate Addition Reaction in Asymmetric Dearomatization of β-Naphthols. Angew. Chem., Int. Ed. 2015, 54, 9523. (15) CCDC 1923035 [(Z)-5a]. (16) CCDC 1922994 [(E)-5aa].

F

DOI: 10.1021/acs.orglett.9b02519 Org. Lett. XXXX, XXX, XXX−XXX