Enantioselective Vinylogous Michael–Aldol Reaction To Synthesize

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

Enantioselective Vinylogous Michael−Aldol Reaction To Synthesize Spirocyclohexene Pyrazolones in Aqueous Media Jinxiu Xu,† Linfeng Hu,† Haipeng Hu,† Shulin Ge,† Xiaohua Liu,† and Xiaoming Feng*,†,‡ †

Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China ‡ Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China Org. Lett. Downloaded from pubs.acs.org by UNIV OF TEXAS AT DALLAS on 03/04/19. For personal use only.

S Supporting Information *

ABSTRACT: An efficient asymmetric vinylogous Michael−aldol domino reaction between α-arylidene pyrazolinones and β,γunsaturated-α-ketoesters catalyzed by a chiral N,N′-dioxide-ScIII complex in aqueous media has been established. A variety of spirocyclohexene pyrazolones with three stereocenters including vicinal tetrasubstituted stereocenters were obtained in excellent yields with good diastereoselectivities and enantioselectivities. A retro-aldol process was observed, which led to epimerization at the spirocyclic quaternary carbon center.

P

Scheme 1. Asymmetric Synthesis of Spirocyclohexene Pyrazolones from α-Arylidene Pyrazolinones

yrazole and pyrazolone derivatives represent a class of valuable five-membered nitrogen heterocyclic compounds, which contain unique structures found in some bioactive natural products and pharmaceuticals.1 Among them, chiral spiropyrazolones show medicinal values, such as antibacterial and antitumor properties.2 Thus, enantioselective synthesis of these compounds has attracted considerable attention in recent years.3 In addition to domino reactions or one-pot sequential reactions of the α,β-unsaturated pyrazolones as the Michael acceptors,4 asymmetric vinylogous γ-addition-initiated formal cycloaddition reactions with α,β-unsaturated pyrazolone5 bearing a γ-hydrogen as nucleophile have been explored for the construction of spirocyclohexene pyrazolones (Scheme 1).6 Initially, the Biju group used the cooperative NHC/DBUcatalyzed formal [3 + 3] annulation between enals and αarylidene pyrazolinones to synthesize spirocyclic adducts.6e Later, TMS-protected prolinol derivatives were used for a vinylogous Michael−aldol sequence to furnish these targets.6a,b In addition, [3 + 3] annulations of MBH carbonates or 2nitroallylic acetates with α-arylidene pyrazolinones catalyzed by hydroquinidine or squaramide were successful for constructing the pyrazolone-fused spirocyclohexenes. 6c,d Nevertheless, the application of β,γ-unsaturated-α-ketoesters as bis-electrophilic C3 synthons were relatively uninvestigated,7 which would afford the desired spirocyclic skeletons with vicinal tetrasubstituted carbon and tert-alcohol centers. Herein, we describe a chiral Lewis acid8-catalyzed vinylogous Michael−aldol domino reaction, affording the titled products in good yields and enantioselectivities. It is noteworthy that the © XXXX American Chemical Society

reaction proceeds in a mixed solvent containing water without basic additives. In addition, control experiments disclose a retro-aldol process that leads to epimerization at the spirocyclic quaternary carbon center. In the initial investigation, β,γ-unsaturated-α-ketoester 1a and α-arylidene pyrazolinone 2a were chosen as the model reaction substrates to optimize the reaction conditions (Table 1). We were pleased to find that the domino reaction went well in the presence of the chiral L-RaAd/ScIII complex in dichloromethane (DCM) at 0 °C, delivering the desired Received: January 15, 2019

A

DOI: 10.1021/acs.orglett.9b00168 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 1. Optimization of the Reaction Conditions

entrya

ligand

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

L-RaAd L-RaAd L-RaAd L-PrAd L-PiAd L-RaMe2 L-RaPr2 L-RatBu L-RaAd L-RaAd L-RaAd L-RaAd

solvent DCM DCM DCM DCM DCM DCM DCM DCM DCM:H2O DCM:H2O DCM:H2O DCM:H2O

yieldb (%)

diastereomeric ratio,c dr

enantiomeric excess, eed (%)

94 79 77 90 92 92 95 98 95 94 70 96

84:16 75:25 84:16 85:15 85:15 86:14 84:16 85:15 84:16 85:15 84:16 85:15

48 7 30 45 33 8 14 16 92 93 74 93

(20:1) (1:1) (1:20) (1:1)

a

Unless otherwise noted, all reactions were performed with Sc(OTf)3/ligand (1/1.05, 10 mol %), 1a (0.10 mmol) and 2a (0.10 mmol) in solvent (1.0 mL) at 0 °C in air for 3 days. bIsolated yield. cAs determined by 1H NMR. dAs determined by HPLC analysis on a chiral stationary phase. e The metal salt was Mg(OTf)2. fThe metal salt was Yb(OTf)3. gThe amount of solvent was 1.05 mL. hThe reaction was performed at 35 °C for 2 days.

Table 2. Substrate Scope of β,γ-Unsaturated-α-Ketoesters

product 3aa in 94% yield with 84:16 diastereomeric ratio (dr) and 48% enantiomeric excess (ee) for the major diastereomer (Table 1, entry 1). When metal salt Sc(OTf)3 was changed to Mg(OTf)2 or Yb(OTf)3, worse results were obtained (see Table 1, entry 1 versus entries 2 and 3). Subsequently, further investigations of the ligands showed that the L-ramipril-derived L-RaAd gave better results than the L-proline-derived L-PrAd and L-pipecolic acid-derived L-PiAd (see Table 1, entry 1 versus entries 4 and 5). Steric hindrance of the amide substituents on the ligand had a significant effect on the outcomes of the reaction. Weakening steric hindrance on the amide moiety from 1-adamantyl group to 2,6-disubstituted phenyl (L-RaMe2 and L-RaPr2) or tertiary butyl group (LRatBu), resulted in much lower enantioselectivities (see Table 1, entry 1 versus entries 6−8). When the effect of solvent was investigated, it was found that water had a dramatic effect on the enantioselectivity (Table 1, entries 9−11). The product could be obtained in 94% yield with 85:15 dr and 93% ee, even a cosolvent system of DCM/H2O (1:1, v/v) was used (Table 1, entry 10). Reducing the amount of DCM (DCM:H2O = 1:20) could also get moderate results (70% yield with 84:16 dr and 74% ee, entry 11). When the reaction was performed at 35 °C, the results obtained were the same as those obtained at 0 °C, and the reaction was completed in less time (Table 1, entry 12 versus entry 10). Thus, we chose the reaction conditions in entry 12 of Table 1 for further studies. With the optimized reaction conditions in hand, we started to investigate the substrate scope of this domino reaction. At first, the reactivity of various β,γ-unsaturated-α-ketoesters 1 was examined (see Table 2). Ketoesters containing isopropyl

a

1

2

entry

R /R

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

C6H5/i-Pr C6H5/Cp 4-FC6H4/Cp 4-BrC6H4/Cp 4-ClC6H4/Cp 3-ClC6H4/Cp 2-ClC6H4/Cp 4-MeC6H4/Cp 3-MeC6H4/Cp 4-MeOC6H4/Cp 3-MeOC6H4/Cp 2-thienyl/Cp 2-naphthyl/Cp C6H5/Me cyclohexyl/Me

b

yield (%) 96 96 95 99 99 96 95 99 97 95 98 97 93 93 85

(3aa) (3ba) (3ca) (3da) (3ea) (3fa) (3ga) (3ha) (3ia) (3ja) (3ka) (3la) (3ma) (3na) (3oa)

diastereomeric ratio,c dr

enantiomeric excess,d ee (%)

85:15 85:15 84:16 85:15 84:16 81:19 85:15 85:15 82:18 85:15 85:15 63:37 82:18 72:28 67:33

93 92 90 90 90 90 87 90 89 89 90 87/90 86 92/75 84/85

a

All reactions were performed with Sc(OTf)3/L-RaAd (1/1.05, 10 mol %), 1 (0.10 mmol) and 2 (0.10 mmol) in DCM/H2O (v/v = 1/1, 1.0 mL) at 35 °C in air for 2 days. bIsolated yield. cAs determined by 1 H NMR. dAs determined by HPLC analysis on a chiral stationary phase. Cp = cyclopentyl.

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DOI: 10.1021/acs.orglett.9b00168 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 3. Substrate Scope of α-Arylidene Pyrazolinones

entrya

R1/R2/R3

1 2 3 4 5 6 7 8 9 10 11 12 13 14

4-FC6H4/Ph/Ph 4-BrC6H4/Ph/Ph 4-ClC6H4/Ph/Ph 3-ClC6H4/Ph/Ph 2-ClC6H4/Ph/Ph 4-MeC6H4/Ph/Ph 3-MeC6H4/Ph/Ph 2-MeC6H4/Ph/Ph 4-MeOC6H4/Ph/Ph 3-MeOC6H4/Ph/Ph 2-MeOC6H4/Ph/Ph piperonyl/Ph/Ph Ph/CH3/Ph Ph/Ph/t-Bu

yieldb (%) 99 94 98 94 96 90 97 96 99 97 70 82 90 60

(3bb) (3bc) (3bd) (3be) (3bf) (3bg) (3bh) (3bi) (3bj) (3bk) (3bl) (3bm) (3bn) (3bo)

diastereomeric ratio,c dr

enantiomeric excess,d ee (%)

82:18 84:16 84:16 81:19 83:17 86:14 86:14 67:33 85:15 85:15 83:17 84:16 67:33 59:41

85 80 80 88 84 87 92 87/88 89 90 94 91 80/86 58/60

a

All reactions were performed with Sc(OTf)3/L-RaAd (1/1.05, 10 mol %), 1 (0.10 mmol) and 2 (0.10 mmol) in DCM/H2O (v/v = 1/1, 1.0 mL) at 35 °C in air for 2 days. bIsolated yield. cAs determined by 1H NMR. dAs determined by HPLC analysis on a chiral stationary phase. Cp = cyclopentyl.

3bo in 60% yield with 59:41 dr and 58/60% ee (Table 3, entry 14). To test the synthetic potential of this reaction, a gram-scale synthesis of 3ba was performed. β,γ-Unsaturated-α-ketoester 1b (2.0 mmol, 0.49 g) reacted smoothly with 2a (2.0 mmol, 0.68 g) under the optimized reaction conditions, giving the corresponding spirocyclohexene pyrazolone 3ba in 96% yield with 85:15 dr and 88% ee (see the Supporting Information (SI) for details). The X-ray crystallography analysis of the product 3ba showed that it consists of both the (5R,6R,8R)and the (5S,6R,8R)-diastereomers (Scheme 2). It was found that isomerization existed at the quaternary carbon center of the spirocycle position. We performed control experiments to elucidate this phenomenon. Starting from spiropyrazolone 3ba with high or low dr, treatment under the standard conditions or in a mixed solvent of dichloromethane and petroleum ether at room temperature for 2 days resulted in equilibration to 3ba

(i-Pr), cyclopentyl (Cp), or methyl (Me) ester substituents could deliver the related products with high enantioselectivity (3aa, 3ba, and 3na; see Table 2, entries 1, 2, and 14), while 3na was provided in a slightly lower dr (72:28). Both electronwithdrawing and electron-donating substituents at different position of β-aryl group of ketoesters were tolerated, yielding the products (3ca−3ka) in excellent yields (95%−99%) with good diastereoselectivities (81:19−85:15) and high enantioselectivities (87%−90% ee) (Table 2, entries 3−11). In comparison, 3ga with a 2-chloro substituent was obtained with a slightly lower ee value (Table 2, entry 7). In addition, 2thienyl and 2-naphthyl-substituted β,γ-unsaturated-α-ketoesters were amenable to the present reaction, but the dr value of 3la reduced to 63:37 while 3ma with 82:18 dr was obtained (Table 2, entries 12 and 13). In addition, alkyl-substituted substrate 1o was tolerated as well, delivering the product 3oa in 85% yield with 67:33 dr and 84/85% ee (Table 2, entry 15). Next, the reaction of ketoester 1b with various α-arylidene pyrazolinones 2 was evaluated (Table 3). With regard to the substituents on the phenyl ring at R1 position of the αarylidene pyrazolinones, those with electron-donating substituents reacted to give slightly higher enantioselectivities than those bearing electron-withdrawing ones (3bg−3bl vs 3bb− 3bf; see Table 3, entries 6−11 vs 1−5). The α-arylidene pyrazolinone 2i with an ortho-methyl group delivered the product 3bi with a lower diastereoselectivity (67:33 dr; entry 8 in Table 3), and α-arylidene pyrazolinone 2l with an electrondonating ortho-methoxy group was converted to the desired product 3bl in a reduced yield (70%) but a higher ee (94% ee; Table 3, entry 11). The reaction of 5-piperonyl-substituted substrate 2m afforded the corresponding product 3bm with good results (Table 3, entry 12). However, when R1 = Me, the reaction did not proceed under standard conditions.9 When R2 = Me, the reaction produced 3bn in 90% yield with 67:33 dr and 80/86% ee (Table 3, entry 13). The N-tert-butyl substituted α-arylidene pyrazolinone delivered the product

Scheme 2. Analysis of the Configuration of 3ba

C

DOI: 10.1021/acs.orglett.9b00168 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

can coordinate with the L-RaAd/ScIII complex to form a transition state with an octahedral geometry. Because of the steric hindrance between the adamantyl group of the ligand LRaAd and the active dienoate species of α-arylidene pyrazolinone 2a, the vinylogous Michael addition occurs preferentially from the β-Si face of 1b, and then follows an intramolecular aldol addition to afford the targeted spiropyrazolone. In summary, we have developed a catalytic asymmetric vinylogous Michael−aldol domino reaction of α-arylidene pyrazolinones with β,γ-unsaturated-α-ketoesters in aqueous media by using a chiral N,N′-dioxide/ScIII complex. This strategy provides a highly efficient and convenient pathway to construct spirocyclohexene pyrazolones with three stereocenters including vicinal tetrasubstituted stereocenters and tertalcohol stereocenter in good results. Water plays an important role in the reaction for benefiting the deprotonation process. Further studies on the application of this catalyst system are underway in our laboratory.

with the same 85:15 dr, while the enantioselectivity was maintained. Therefore, it is rationalized that a retro-aldol process was occurring that leads to epimerization, and the chiral catalyst is in charge of the facial selectivity in the initial vinylogous γ-conjugate addition step. The diastereoselectivity shown in the aforementioned tables might reflect the thermodynamic stability of the diastereomers rather than the stereocontrol of the chiral catalyst in the second aldol addition step. The role of water was probed by 1H NMR spectra analysis (see the SI for details). It showed that there was a quick equilibrium between dienolate intermediate and α-arylidene pyrazolinone via deprotonating γ-hydrogen of pyrazolinone in the presence of water. Thus, this domino reaction occurred efficiently in the absence of an additional base which was different from most of the previous formal [3 + 3] annulation reactions.6 Moreover, chiral N,N′-dioxide L-RaAd acted as a tetradentate ligand to form cyclic scandium(III) complex in the presence of water, which was bridged by the oxygen of two hydroxyl ions to form an unusual dinuclear structure detected from X-ray crystal analysis (Figure 1). Nevertheless, the

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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.9b00168. Experimental procedures, full spectroscopic data for all new compounds, and 1H and 13C NMR and HPLC spectra (PDF) Accession Codes

CCDC 1863782 and 1888176 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, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

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

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge the National Natural Science Foundation of China (Nos. 21890723 and 21772127) for financial support

Figure 1. Graphical depiction of the possible reaction mechanism.

relationship of ee values between the ligand and the product was studied (for details, see the SI), and there was no nonlinear effect in the current catalytic system, implying that the enantiodetermining active catalyst was likely a monochiral N,N′-dioxide-scandium complex. The hydroxyl ions might act as a potential base to accelerate the deprotonation of αarylidene pyrazolinone 2 and release the active monoscandium(III) catalyst for the activation of the electrophile. As discussed above and based on the previous studies of our group,10,11 a plausible mechanism was proposed (Figure 1). At first, two carbonyl oxygens of β,γ-unsaturated-α-ketoester 1b

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DOI: 10.1021/acs.orglett.9b00168 Org. Lett. XXXX, XXX, XXX−XXX

Letter

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DOI: 10.1021/acs.orglett.9b00168 Org. Lett. XXXX, XXX, XXX−XXX