Organocatalytic Enantioselective 1,3-Difunctionalizations of Morita

Letter Cite This: Org. Lett. 2018, 20, 6279−6283

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Organocatalytic Enantioselective 1,3-Difunctionalizations of Morita−Baylis−Hillman Carbonates Zhi-Chao Chen,† Peng Chen,† Zhi Chen,† Qin Ouyang,‡ Hua-Ping Liang,*,‡ Wei Du,† and Ying-Chun Chen*,†,‡ †

Org. Lett. 2018.20:6279-6283. Downloaded from pubs.acs.org by UNIV OF SUNDERLAND on 10/05/18. For personal use only.

Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China ‡ State Key Laboratory of Trauma, Burn and Combined Injury, and College of Pharmacy, Third Military Medical University, Shapingba, Chongqing 400038, China S Supporting Information *

ABSTRACT: The in-situ-generated zwitterionic allylic ylides between Morita−Baylis−Hillman carbonates from isatins and chiral tertiary amine catalysts underwent highly regioselective and enantioselective 1,3-oxo-ethynylation or 1,3-aminosulfenylation reactions with silyl ethynyl-1,2-benziodoxol3(1H)-ones or N-(aryl or alkylthio)imides, respectively, giving densely functionalized products bearing a quaternary stereogenic center. An array of diversely structured scaffolds were efficiently constructed from the products, showing the synthetic versatility of the current catalytic strategy.

T

ylide species II, which are widely applied as 3C partners in the annulations with electrophilic reagents, affording structurally diverse carbon or heterocyclic frameworks (Scheme 1b).5 Nevertheless, the potential asymmetric 1,3-difunctionalizations of MBHCs in a noncyclization pathway, such as those outlined in Scheme 1c, which would lead to differently functionalized scaffolds, still remain to be disclosed. Hypervalent iodine reagents, especially the cyclic ones, are stable and particularly valuable for electrophilic introduction of diverse functional groups.6 As alkynes are widely applied in synthetic chemistry and other fields, ethynylbenziodoxol(on)e (EBX) reagents have been conveniently employed in an array of alkynylation reactions with carbon-centered or heterocentered nucleophiles.7 Nevertheless, 2-iodobenzoic acid is usually produced as a stoichiometric byproduct. The Yoshikai group first combined both counterparts in palladium-catalyzed condensation of N-aryl imines and alkynylbenziodoxolones to form furan products.8 Subsequently, Waser and co-workers disclosed copper-catalyzed 1,1-oxo-alkynylation of diazo compounds.9 On the other hand, although the electrophilic introduction of alkynyl group with EBX reagents has been demonstrated to be quite successful, the related asymmetric versions are still limited, often suffering from narrow substrate scope and low enantiocontrol.10 To address these deficiencies, here, we would like to uncover an unprecedented asymmetric 1,3-oxy-ethynylation reaction of MBHCs from isatins and EBX reagents under metal-free conditions, delivering multifunctional products bearing an all-carbon-based quaternary stereogenic center.11

he development of synthetic protocols to access chiral architectures with broad structural diversity from readily available starting materials is very attractive, but challenging in both the organic and medicinal chemistry fields.1 The Morita− Baylis−Hillman (MBH) reaction, condensed from activated alkenes and carbonyl compounds catalyzed by Lewis bases (LBs), can efficiently produce densely functionalized materials, which also trigger enormous interest in latent asymmetric transformations.2 Apart from the reactions based on metal catalysis, LBs, such as tertiary phosphines and amines, play an important role.3 As illustrated in Scheme 1a, a common strategy involves the nucleophilic attack of LBs to Morita− Baylis−Hillman carbonates (MBHCs), to generate electrophilic onium salts I, which undergo γ-regioselective asymmetric allylic alkylations with nucleophiles.4 On the other hand, intermediates I can be deprotonated to produce zwitterionic Scheme 1. Lewis Base (LB)-Catalyzed Asymmetric Transformation Strategies for Morita−Baylis−Hillman Carbonates (MBHCs)

Received: August 29, 2018 Published: September 26, 2018 © 2018 American Chemical Society

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DOI: 10.1021/acs.orglett.8b02764 Org. Lett. 2018, 20, 6279−6283

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With the optimal catalytic conditions in hand, the substrate scope and limitations of this new transformation were investigated. The results are summarized in Scheme 2. A

The initial reaction of MBHC 1a and trimethylsilyl EBX 2a gave a relatively complex mixture catalyzed by either DABCO or DMAP (20 mol %) at ambient temperature, and no apparent conversions were observed with Ph3P. Fortunately, a cleaner reaction was obtained at −20 °C catalyzed by DABCO, and the thermally more stable Z-selective product 3a,12 proceeding in electrophilic γ-ethynylation, followed by αcarboxylation, was isolated in a fair yield after 72 h (Table 1,

Scheme 2. Substrate Scope and Limitations of Enantioselective 1,3-Oxo-Ethynylation Reactionsa,b,c

Table 1. Screening Conditions of 1,3-Oxy-Ethynylation Reactions of MBHC 1a and EBX Reagents 2aa

entry

C

2

solvent

1d 2d 3d 4d 5d 6 7 8 9 10 11 12 13e 14f 15e,g

DABCO C1 C3 C2 C4 C4 C4 C4 C4 C4 C4 C4 C4 C4 C4

2a 2a 2a 2a 2a 2a 2a 2a 2a 2b 2c 2d 2b 2b 2b

THF THF THF THF THF THF DCM MeCN PhCF3 THF THF THF THF THF THF

yieldb (%)

enantiomeric excess, eec (%)

30 35 16 47 31 68 20 41 58 89 12

4 15 −64 86 82 81 76 73 88 80

77 76 64

91 86 84

a Unless noted otherwise, reactions were performed with MBHC 1a (0.1 mmol), EBX 2 (0.2 mmol), amine C (20 mol %) in solvent (1.0 mL) at −20 °C for 72 h. bIsolated yield. cDetermined by HPLC analysis on a chiral stationary phase. dWith 0.15 mmol of EBX 2. e With 15 mol % C4. fWith 10 mol % C4. gAt −30 °C.

entry 1).13 Subsequently, we tested the potential asymmetric version by using cinchona-derived catalysts.14 While both α-IC (C1) and β-ICD (C3) with a free OH group gave very poor results (Table 1, entries 2 and 3), the enantioselectivity was significantly improved by using O-methylated C2 and C4, whereas the yields were not satisfactory (Table 1, entries 4 and 5). Inferior results were observed when other modified catalysts were applied.12 Both yield and enantioselectivity were improved catalyzed by C4 by employing larger amounts of EBX 2a (Table 1, entry 6). Changing solvent was not successful (Table 1, entries 7−9). Other silylated EBX reagents were explored (Table 1, entries 10−12), and high yield and enantiocontrol were attained with TES-EBX 2b (Table 1, entry 10). Moreover, better enantiocontrol was achieved with slightly lower catalyst loadings (Table 1, entry 13), while the data were worse with 10 mol % C4 (Table 1, entry 14). In addition, poorer results were observed at a lower temperature (Table 1, entry 15).

a

Unless noted otherwise, reactions were performed with MBHC 1 (0.1 mmol), EBX reagent 2 (0.2 mmol), catalyst C4 (15 mol %) in THF (1.0 mL) at −20 °C for 72 h. bIsolated yield. cThe ee value was determined by HPLC analysis on a chiral stationary phase. dAt −30 °C.

comparable enantiomeric excess (ee) value for product 3b was obtained with a MBHC bearing an ethyl ester group. Pleasingly, excellent data were afforded in the reactions of 1a and EBX reagents 2 with either an electron-donating or electron-withdrawing group (products 3c−3e). High enantioselectivity was produced for the MBHCs 1 with electrondonating substituents on the aryl ring (products 3f−3i); nevertheless, slightly diminished enantiocontrol was generally delivered for the MBHCs 1 possessing electron-withdrawing groups (products 3j−3q). In addition, good results were attained for MBHCs 1 with either an N-benzyl or N-allyl group 6280

DOI: 10.1021/acs.orglett.8b02764 Org. Lett. 2018, 20, 6279−6283

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Organic Letters

Interestingly, as outlined in Scheme 4, the enol 2-iodobenzoate group of 3c was easily hydrolyzed in the presence of DABCO,

(products 3r and 3s). The MBHCs derived from 7-azaisatins were explored, while moderate data were produced (products 3t and 3u). The current strategy could be efficiently expanded to other types of electrophiles including nucleofuge, for example, in an enantioselective 1,3-amino-sulfenylation reaction. The product 5a was produced between the MBHC from isatin and ethyl acrylate and N-(phenylthio)succinimide15 4a in a moderate yield with excellent enantiocontrol catalyzed by amine C2 (see Scheme 3).12 Even a slightly higher yield was obtained for the

Scheme 4. Synthetic Transformations of Multifunctional 1,3-Difunctionalization Productsa

Scheme 3. Substrate Scope of Enantioselective 1,3-AminoSulfenylation Reactionsa,b,c

a

a Conditions for each step are described as follows: (a) DABCO, H2O, THF, 40 °C, 36 h; (b) (i) MeNHNH2·HCl, K2CO3, THF, 0 °C, 2 h; (ii) MeOH, 60 °C, 12 h; (c) Cu(OTf)2 (20 mol %), NEt3, DCM, 30 °C, 24 h.; (d) (i) NH2OH·HCl, K2CO3, THF, 0 °C-rt, overnight; (ii) MgSO4, toluene, 90 °C, 10 h; (e) 2-iodopyridine, PdCl2(TPP)2 (10 mol %), CuI (15 mol %), DIPEA, 55 °C, THF, 36 h; (f) Raney Ni (20 wt %), H2 (1 atm), EtOH/THF, 35 °C, 40 h; (g) BnN3, CuI (10 mol %), DIPEA, THF, 40 °C, 36 h; and (h) MeNHNH2, THF, 0 °C, 1 h.

product 5b bearing a t-butyl ester group. An array of N(arylthio)succinimides with either an electron-withdrawing group or an electron-donating group were well-tolerated, and the corresponding products 5c−5g were generally obtained in good yields with outstanding enantioselectivity. An N(benzylthio)succinimide also was compatible at a slightly lower temperature, delivering 5h with good data. In addition, similar high enantiocontrol for product 5i was observed by using a phthalimide-based sulfenylation reagent. On the other hand, high enantioselectivity for products 5j−5l was delivered from the MBHCs bearing either an electron-withdrawing group or an electron-donating group on the aryl ring, even at a 1.0 mmol scale.16 The multiple functionalities of the products enabled the latent transformations to construct a diversity of scaffolds, some of which are not readily available by other protocols.

and a domino intramolecular “5-exo-dig” hydrooxygenation reaction was followed to give product 6 in excellent yield.17 In addition, a pyrazole derivative 7 was produced by treating 3c with N-methylhydrazine, followed by cyclization,18 which further underwent a “6-endo-dig” hydrooxygenation process to generate an intriguing bicyclic hydropyrano[2,3-c]pyrazole skeleton 8 under the catalysis of Cu(OTf)2.17 Moreover, an unexpected decarboxylation reaction occurred by heating the oxime intermediate from 3c with MgSO4, providing a substituted acetonitrile derivative 9 in high yield. On the other hand, some chemoselective reactions could be conducted involving the ethynyl group. Although the substituted EBX reagents6,7 failed to participate in the current reaction, the Sonagashira coupling was conveniently conducted with adduct 3c and 2-iodopyridine, affording product 10 in good yield. A vinyl functionality was effectively constructed through mild Raney Ni-catalyzed hydrogenation, and product 11 was obtained after treatment with N-methylhydrazine. Furthermore, a sequential click reaction and pyrazolation process yielded a druglike substance 13 in high efficacy. On the other

Unless noted otherwise, reactions were performed with MBHC 1 (0.1 mmol), N-thio imide reagent 4 (0.2 mmol), catalyst C2 (20 mol %) in THF (1.0 mL) at −20 °C for 72 h. bIsolated yield. cThe ee value was determined by HPLC analysis on a chiral stationary phase. d At −25 °C. eAt −10 °C. fAt a 1.0 mmol scale.

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hand, product 5i easily underwent hydrazinolysis to give stable enamine 14 in the presence of N-methylhydrazine. Based on labeling experimental and DFT computational calculation studies,12 a catalytic 1,3-oxo-ethynylation process is proposed in Scheme 5. DABCO reacted with MBHC 1a to

CCDC 1834182, 1834183, 1834184 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], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.

Scheme 5. Proposed Catalytic Mechanism of 1,3-OxoEthynylation Reaction

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (H.-P. Liang). *E-mail: [email protected] (Y.-C. Chen). ORCID

Qin Ouyang: 0000-0002-1161-5102 Ying-Chun Chen: 0000-0003-1902-0979 Funding

We are grateful for the financial support from the NSFC (No. 21572135) and the Open Project of the State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University (No. SKLKF201601). Notes

The authors declare no competing financial interest.

generate ammonium salt I and t-butoxide, and zwitterion II and t-butanol would be generated after deprotonation. In addition, silyl EBX 2b would undergo desilylation to afford alkyne anion I′ assisted by t-butoxide,12 and subsequent protonation would give the ethynyl-1,2-benziodoxol-3(1H)one III.7a Then Michael-type addition of II to alkyne III would deliver complex IV after eliminating 2-iodobenzoate. The subsequent 1,2-hydride-shift would occur through the transition state IV-TS assisted by carboxylate group.12 Michael addition between complex V produced species VI, which finally provided the thermally more stable product Z-3a after releasing DABCO. In conclusion, we demonstrated that the in-situ-generated zwitterionic N-allylic ylides between MBHCs from isatins and chiral tertiary amines could undergo highly regioselective and enantioselective 1,3-oxo-ethynylation reactions with readily available silyl ethynyl-1,2-benziodoxol-3(1H)-ones. This 1,3difunctionalization strategy was efficiently expanded to enantioselective 1,3-amino-sulfenylation reactions with Narylthio or alkylthio imide reagents. In both cases, the electrophilic and nucleophilic counterparts were finely merged into the MBHC partners, producing a spectrum of chiral products with dense functionalities. Moreover, versatile latent transformations rendered the construction of enantioenriched architectures with high scaffold diversity, which might be valuable in organic and medicinal chemistry. The current strategy would be applicable to more difunctionalization reactions of MBH derivatives.

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REFERENCES

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02764. Complete experimental procedures and characterization of new products; NMR spectra and HPLC chromatograms; labeling experiments and the detailed DFT calculations (PDF) 6282

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