Direct Catalytic Enantioselective Vinylogous Aldol Reaction of Allyl

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Direct Catalytic Enantioselective Vinylogous Aldol Reaction of Allyl Ketones to Pyrazole-4,5-diones Bidisha Ray, and Santanu Mukherjee J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01566 • Publication Date (Web): 19 Jul 2018 Downloaded from http://pubs.acs.org on July 19, 2018

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The Journal of Organic Chemistry

Bidisha Ray and Santanu Mukherjee* Department of Organic Chemistry, Indian Institute of Science, Bangalore - 560012, India Supporting Information Placeholder

ABSTRACT: The first catalytic enantioselective vinylogous nucleophilic addition to pyrazole-4,5-diones is reported. Using quinine-derived bifunctional tertiary amino-amide as the catalyst, this direct aldol reaction of allyl ketones is shown to proceed exclusively in γ- and E-selective manner to generate pyrazolone derivatives, bearing an oxygen-containing quaternary stereogenic center, in good yields with moderate to high enantioselectivities (up to 97:3 er).

Scheme 1. Enantioselective Reactions of Pyrazolones Transmission of electronic effect through π-system plays an important role in determining the reactivity of unsaturated organic compounds. Termed as the principle of vinylogy,1 this phenomenon allows for remote functionalization where bond formation can take place away from the parent functional group.2 However, controlling regioselectivity has remained a challenge for reactions involving such unsaturated compounds, especially when employed as nucleophile. Consequently, a majority of the applications of vinylogous nucleophilic reactivity has been limited to cyclic systems.3 For acyclic carbonyl compounds, vinylogous reactivity is dominated by Mukaiyama-type reactions involving dienol silyl ethers3,4 and suffers from unfavorable atom- as well as step-economy.5 Direct vinylogous reactions involving unsaturated carbonyl compounds without having to preform the enolate equivalent is highly desirable. However, the low electron density at the γ-position of dienolates hinders their vinylogous reactivity6 and generally favors α-selective reactions. Modified substrates containing a bulky substituent at the α-position is often used for achieving the desired γ-selectivity.7 Irrespective of these challenges, deconjugated carbonyl compounds such as allyl ketones have recently emerged as a useful class of acyclic vinylogous nucleophile in asymmetric synthesis, primarily through the work of Huang, Jiang and co-workers. In 2013, this group developed the first catalytic enantioselective direct vinylogous aldol reaction between allyl ketones and isatins.8 Subsequent to this report and owing to their easy accessibility, allyl ketones have been employed as vinylogous nucleophile for a handful of other catalytic transformations.9

Pyrazolones are a privileged class of compounds which found importance due to their diverse applications in pharmaceutical, analytical and dye chemistry.10 This five-membered aza-heterocycle possesses multiple reactive sites and gained considerable attention in asymmetric synthesis. The most common application of pyrazolin-5-ones involves its C-4 nucleophilicity (Scheme 1A) and a fairly large number of catalytic enantioselective reactions have been developed.11 Pyrazole-4,5-diones, on the other hand, is electrophilic at their C-4 position (Scheme 1A). During the past year, Enders and co-workers have developed a few catalytic enantioselective transformations involving pyrazole-4,5-diones and their corresponding ketimines.12 While the scope

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of nucleophiles ranges from cyanides to indoles and naphthols, addition of a vinylogous nucleophile to pyrazole-4,5diones is yet to be achieved. Considering the widespread utility of pyrazolones and as part of our own research program on vinylogous reactivity of deconjugated carbonyl compounds,13 we became interested in developing a direct vinylogous aldol reaction of allyl ketones to pyrazole-4,5-diones. Such a reaction is expected to furnish densely functionalized pyrazolin-5-one derivatives bearing an oxygen-containing quaternary stereogenic center.14 Identification of a suitable catalyst system was reckoned to hold the key to the success of this reaction. We envisioned a dual activation of allyl ketones and pyrazole-4,5-diones through bifunctional Brønsted base/hydrogen bonding catalyst (Scheme 1B).15 While Brønsted basic tertiary amine moiety of the catalyst was expected to enolize allyl ketones through removal of its acidic α-proton, LUMO-lowering activation of pyrazole-4,5-diones was envisaged through Hbonding from the Brønsted acidic part of the catalyst. We were cognizant of the potential regioselectivity issues associated with this reaction and the mixed (α- vs. γ-) selectivity previously observed under the influence of similar catalyst systems.16 Nonetheless, considering the sterically hindered nature of the electrophilic site at the C-4 of pyrazole-4,5-diones, we believed the proposed catalyst system would favor the desired vinylogous reactivity of allyl ketones. Herein we describe the successful execution of this strategy for the development of a catalytic enantioselective and exclusively γ- and E-selective addition of allyl ketones to pyrazole-4,5-diones.

Our study was initiated with the objective of optimizing the catalyst and reaction conditions for the proposed vinylogous aldol reaction. Toward this goal, addition of allyl phenyl ketone (2a) to 1-(tert-butyl)-3-methyl-1H-pyrazole4,5-dione (1a) was chosen as the model reaction (Table 1). Lack of any reaction when 1a and 2a were stirred in a solution of diethylether at 25 °C, even after 24 h (entry 1), facilitated the catalyst screening. We were pleased to note that the same reaction, when conducted in the presence of 10 mol % of quinine-derived tertiary aminothiourea catalyst I, the desired aldol product 3aa was formed in 71% yield, not only as a single regioisomer (α- vs. γ-) but also as a single diastereomer (>20:1 E/Z) with moderate enantioselectivity (entry 2). Use of the corresponding urea derivative II or 1,2diphenylethylenediamine-derived thiourea III as catalyst failed to improve the er (entries 3-4). However, significant improvement in the er was observed when quinine-derived 3,5-bis(trifluoromethyl)benzamide IV was employed as the catalyst, albeit at the expense of reaction rate (entry 5). This class of bifunctional tertiary amino-amides has recently emerged as a very useful class of single H-bond donor catalyst for a number of enantioselective transformations.17 Lower catalytic activity of amide IV compared to (thio)ureas (I-III) is not completely unexpected considering the number of hydrogen bond donors in these two types of catalysts. The related 4-trifluoromethylbenzamide V turned out to be an inferior catalyst compared to IV, both in terms of activity as well as enantioselectivity (entry 6). Reaction

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using catalyst IV in various solvents (entries 7-10) revealed cyclopentyl methyl ether (CPME) as the optimum and furnished the product in 79% yield with 96:4 er. A slight increase in yield was observed when carrying out the reaction at lower concentration (entry 11). Lowering of reaction temperature, although reduced the reaction rate drastically, did not offer any positive influence on the er (entry 12). Table 1. Catalyst Screening and Reaction Optimizationa

entry

cat.

solvent

t (h)

yield (%)b

erc

1

-

Et2O

24

20:1 E/Z ratio. bYields correspond to the isolated yield. cEnantiomeric ratio (er) was determined by HPLC analysis on a chiral stationary phase. dReaction at 0.05 M initial concentration. eReaction at 0 °C. CPME = cyclopentyl methyl ether.

The optimum catalyst and reaction conditions thus identified (Table 1, entry 11) were extended to other substrate combinations. The direct vinylogous addition of various allyl ketones (2) to 1-(tert-butyl)-3-methyl-1H-pyrazole-4,5dione (1a) was first undertaken (Table 2A). We were pleased to note that allyl aryl ketones having electronically tuned substituents at 3- or 4-position of the aryl ring underwent facile aldol reaction to generate the products in uniformly high yields and enantioselectivities (entries 1-10). In contrast, products were formed with low to modest er when allyl aryl ketones bearing ortho-substituents on the aryl ring were used as the substrate (entries 11-15). Carrying out these reactions at lower temperature did not help in improving the enantioselectivity. This is a rather common phenomenon for reactions with allyl aryl ketones bearing ortho-substituents, and has already been documented in the literature.8,9 While further studies are required to pinpoint


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the exact reason for low enantioselectivities with these substrates, this is possibly due to the steric crowding offered by ortho-aryl substituents. Along this line of observation, product (3aq) derived from allyl 1-naphthyl ketone (2q) was also formed with low er (entry 17). However, heteroaryl substituents such as thiophene (2r) and dioxolane (2s) on the allyl ketone afforded the products in good yield and er (entries 18-19). Alkyl allyl ketones are more challenging substrates compared to the allyl aryl ketones due to the presence of two sets of non-equivalent and enolizable αprotons. We were happy to see that alkyl allyl ketones could also be used as substrate and include both linear (2t) and branched (2u) alkyl group. In both these cases, the single regioisomeric products were formed in good yield but with similar enantioselectivity (entries 20-21). Substituents on pyrazole-4,5-diones were subsequently examined (Table 2B). However, in all these cases the products were generally obtained with moderate er. It must be noted that, in each of the above cases, the product was formed as a single regioisomer and diastereomer (>20:1 E/Z). Table 2. Scope of the Direct Enantioselective Vinylogous Aldol Reactiona

For reactions proceeding with low enantioselectivity, product er can be enriched through crystallization. For example, a single recrystallization led to the isolation of X-ray diffraction quality crystals of 3am with >99:1 er and allowed the unambiguous determination of its absolute configuration through anomalous dispersion X-ray diffraction analysis (Figure 1). The same absolute configuration (R) was tentatively assigned to the remaining examples by analogy, assuming the same catalytic mechanism is operative.

Figure 1. Absolute configuration of 3am and its X-ray structure with thermal ellipsoids at 50% probability. Having tested the substrate generality of our protocol, we decided to showcase its scalability. Hence, we carried out a reaction between 1a and 2a on 1.0 mmol scale using only 5 mol % catalyst IV (Scheme 2). While longer time was required for completion of the reaction, the desired product was obtained with the same level of enantioselectivity as the small scale reaction. In this experiment 90% catalyst recovery was possible through column chromatography and the recovered catalyst maintained the same level of efficacy. In addition to the scalability, synthetic elaboration of 3aa was also demonstrated (Scheme 2). Controlled hydrogenation using 5 mol % of Pd/C for 5 h furnished hydroxyketone 4 in 92% yield. Prolonged hydrogenation using 15 mol % Pd/C, on the other hand, delivered the corresponding diol 5 as a single diastereomer in 95% yield. Treatment of 3aa with H2O2 under Weitz−Scheffer epoxidation18 conditions led to the formation of epoxy ketone in near quantitative yield, but with modest dr. All these transformations proceeded without any erosion of stereochemical integrity of the parent stereogenic center. Scheme 2. Large-Scale Synthesis of 3aa and its Synthetic Transformations

aReactions

were carried out on a 0.1 mmol scale. Yields correspond to the isolated product after chromatographic purification. bEnantiomeric ratio (er) was determined by HPLC analysis on stationary phase chiral column (see the Supporting Information). cReaction using III as the catalyst.



In conclusion, we have developed the first catalytic enantioselective vinylogous aldol reaction of pyrazole-4,5-diones. In fact, this is the first example of an enantioselective addition of any vinylogous nucleophile to pyrazole-4,5-diones. Catalyzed by a quinine-based bifunctional tertiary amino-amide derivative, this direct enantioselective addition of allyl ketones to pyrazole-4,5-diones proceeds in exclusively γ- and E-selective manner. The products – pyrazolin-5-one derivatives, bearing an oxygen-containing quaternary stereogenic center, are formed in good yields with moderate to high enantioselectivities.

General Information. Infrared (FT-IR) spectra were recorded on Perkin Elmer Spectrum BX spectrophotometer and Bruker alfa FT-IR, νmax in cm–1. NMR spectra were recorded on Bruker Ultrashield spectrometer at 400 MHz (for 1H NMR) and 100 MHz (for 13C NMR). Chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance as internal standard (CDCl3: δ 7.26 for 1H NMR and CDCl3: δ 77.00, for 13C NMR). For 1H NMR, data are reported as follows: chemical shift, multiplicity (s = singlet, br s = broad singlet, d = doublet, dd = double doublet, t = triplet, q = quartet, dt = doublet of triplets, m = multiplet), coupling constants (Hz) and integration. High resolution mass spectrometry was performed on Micromass Q-TOF Micro instrument. Optical rotations were measured on JASCO P-2000 polarimeter. Melting points were measured using ANALAB μ-Thermocal 10 melting point apparatus. All melting points were measured in open glass capillary and values are uncorrected. Enantiomeric ratios were determined by Shimadzu LC-20AD HPLC instrument and SPD-20A UV/Vis detector using stationary phase chiral columns (25 cm × 0.46 cm) in comparison with authentic racemic compounds. Unless stated otherwise, all reactions were carried out with distilled and dried solvents under an atmosphere of argon in oven (120 °C) dried glassware with standard vacuum line techniques. Organic solvents used for carrying out reactions were dried using standard methods. All work up and purification were carried out with reagent grade solvents in air. Thin layer chromatography was performed using Merck silica gel 60 F254 pre-coated plates (0.25 mm). Column chromatography was performed using silica gel (230-400 or 100-200 mesh). Catalyst Preparation and Characterization. Catalyst IV was synthesized according to previously reported procedure.17a General Procedure for the Direct Catalytic Enantioselective Vinylogous Aldol Reaction of Allyl Ketones to Pyrazole-4,5-diones. In an oven-dried reaction tube, pyrazole-4,5-dione 1 (0.1 mmol, 1.0 equiv), allyl ketone 2 (0.15 mmol, 0.15 equiv) and catalyst IV (0.01 mmol, 0.1 equiv) were taken along with 2.0 mL CPME. The resulting solution was stirred at 25 °C until TLC showed complete consumption of 1. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel (100-200 mesh) column chromatography to obtain the desired product.

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(R,E)-2-(tert-Butyl)-4-hydroxy-5-methyl-4-(4-oxo-4phenylbut-2-en-1-yl)-2,4-dihydro-3H-pyrazol-3-one (3aa). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 3aa as a colorless oil (25.7 mg, 0.082 mmol, 82% yield). Rf = 0.35 (30% EtOAc in petroleum ether). FT-IR (neat): ν 3580, 3322, 2930, 2360, 1673, 1610, 1567, 1425, 1363, 1231, 1182, 1022, 876 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.88-7.90 (m; 2H), 7.57 (t, J = 7.4 Hz; 1H), 7.46 (t, J = 7.5 Hz; 2H), 6.97 (d, J = 15.3 Hz; 1H), 6.63-6.71 (m; 1H), 3.87 (s; 1H), 2.72-2.82 (m; 2H), 2.09 (s; 3H), 1.41 (s; 9H); 13C NMR (100 MHz, CDCl3): δ 189.8, 174.5, 158.6, 138.8, 137.2, 133.0, 130.4, 128.62, 128.56, 79.2, 57.8, 39.4, 28.0, 13.3; HRMS (ESI+): Calcd for C18H22N2O3Na ([M + Na]+): 337.1528, found: 337.1526; [α]D22 +221.3 (c 1.00, CHCl3) for an enantiomerically enriched sample with 96:4 er. The enantiomeric ratio was determined by HPLC analysis using Phenomenex Cellulose-1 column (254 nm, n-Hexane/EtOH = 95:5, 1.0 mL/min, τminor = 10.32 min, τmajor = 11.71 min). Absolute stereochemistry of 3aa is assigned in analogy with 3am. (R,E)-2-(tert-Butyl)-4-hydroxy-5-methyl-4-(4-oxo-4(p-tolyl)but-2-en-1-yl)-2,4-dihydro-3H-pyrazol-3-one (3ab). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 3ab as a colorless sticky oil (26.0 mg, 0.079 mmol, 79% yield). Rf = 0.35 (30% EtOAc in petroleum ether). FT-IR (neat): ν 3583, 3342, 2927, 2362, 1683, 1618, 1567, 1435, 1363, 1221, 1182, 1022, 976 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 8.1 Hz; 2H), 7.25 (d, J = 7.9 Hz; 2H), 6.98 (d, J = 15.3 Hz; 1H), 6.62-6.69 (m; 1H), 2.72-2.84 (m; 2H), 2.41 (s; 3H), 2.09 (s; 3H), 1.40 (s; 9H); 13C NMR (100 MHz, CDCl3): δ 189.3, 174.8, 159.0, 143.9, 138.4, 134.7, 130.3, 129.3, 128.7, 79.5, 57.7, 39.2, 28.0, 21.6, 13.2; HRMS (ESI+): Calcd for C19H24N2O3Na ([M + Na]+): 351.1685, found: 351.1685; [α]D22 +352.7 (c 1.00, CHCl3) for an enantiomerically enriched sample with 95:5 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IE column (254 nm, n-Hexane/EtOH = 90:10, 1.0 mL/min, τmajor = 14.33 min, τminor = 16.66 min). Absolute stereochemistry of 3ab is assigned in analogy with 3am. (R,E)-2-(tert-Butyl)-4-hydroxy-4-(4-(4-methoxyphenyl)-4-oxobut-2-en-1-yl)-5-methyl-2,4-dihydro-3Hpyrazol-3-one (3ac). Purification by silica gel (100-200 mesh) column chromatography (40% EtOAc in petroleum ether) afforded 3ac as a colorless oil (27.0 mg, 0.078 mmol, 78% yield). Rf = 0.20 (30% EtOAc in petroleum ether). FT-IR (neat): ν 3342, 2977, 1687, 1598, 1512, 1424, 1360, 1259, 1173, 1025 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 8.9 Hz; 2H), 6.99 (d, J = 15.3 Hz; 1H), 6.93 (d, J = 8.4 Hz; 2H), 6.63-6.69 (m; 1H), 4.61 (s; 1H), 3.87 (s; 3H), 2.73-2.84 (m; 2H), 2.09 (s; 3H), 1.40 (s; 9H); 13C NMR (100 MHz, CDCl3): δ 188.0, 174.7, 163.5, 137.8, 130.9, 130.1, 113.8, 79.5, 57.7, 55.4, 39.2, 28.0, 13.3; HRMS (ESI+): Calcd for C19H24N2O4Na ([M + Na]+): 367.1634, found: 367.1631; [α]D22 +340.6 (c 1.00, CHCl3) for an enantiomerically enriched sample with 95.5:4.5 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IE column (254 nm, n-Hexane/EtOH = 85:15, 1.0 mL/min, τmajor = 16.06 min, τminor = 17.79 min). Absolute stereochemistry of 3ac is assigned in analogy with 3am.


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(R,E)-2-(tert-Butyl)-4-(4-(4-chlorophenyl)-4-oxobut2-en-1-yl)-4-hydroxy-5-methyl-2,4-dihydro-3H-pyrazol-3-one (3ad). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 3ad as a colorless oil (25.0 mg, 0.072 mmol, 72% yield). Rf = 0.40 (30% EtOAc in petroleum ether). FT-IR (neat): ν 3580, 3341, 2928, 2857, 1687, 1603, 1580, 1357, 1017, 1093, 1010 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.85 (d; J =8.6, 2H), 7.43 (d; J =8.6, 2H), 6.92-6.96 (m; 1H), 6.66-6.73 (m; 1H), 4.46 (s; 1H), 2.71-2.83 (m; 2H), 2.08 (s; 3H), 1.40 (s; 9H); 13C NMR (100 MHz, CDCl3): δ 188.5, 174.6, 158.9, 139.5, 135.5, 130.0, 129.9, 129.0, 79.3, 57.8, 39.3, 28.0, 13.2; HRMS (ESI+): Calcd for C18H21ClN2O3Na ([M + Na]+): 371.1138, found: 371.1135; [α]D22 +224.3 (c 1.00, CHCl3) for an enantiomerically enriched sample with 96.5:3.5 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IE column (254 nm, n-Hexane/EtOH = 90:10, 1.0 mL/min, τmajor = 10.05 min, τminor = 11.85 min). Absolute stereochemistry of 3ad is assigned in analogy with 3am. (R,E)-4-(4-(4-Bromophenyl)-4-oxobut-2-en-1-yl)-2(tert-butyl)-4-hydroxy-5-methyl-2,4-dihydro-3H-pyrazol-3-one (3ae). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 3ae as a colorless oil (30.0 mg, 0.076 mmol, 76% yield). Rf = 0.40 (30% EtOAc in petroleum ether). FT-IR (neat): ν 3574, 3320, 2926, 2853, 1680, 1622, 1553, 1428, 1374, 1218, 1100, 1024, 971 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.75-7.79 (m; 2H), 7.59-7.63 (m; 2H), 6.93 (d, J =15.3; 1H), 6.66-6.73 (m; 1H), 4.40 (s; 1H), 2.71-2.83 (m; 2H), 2.08 (s; 3H), 1.40 (s; 9H); 13C NMR (100 MHz, CDCl3): δ 188.7, 174.6, 158.8, 139.6, 135.9, 131.9, 130.1, 129.8, 128.2, 79.3, 57.8, 39.2, 28.0, 13.3; HRMS (ESI+): Calcd for C18H21BrN2O3Na ([M + Na]+): 415.0633, found: 415.0634; [α]D22 +340.6 (c 1.00, CHCl3) for an enantiomerically enriched sample with 96:4 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IE column (254 nm, n-Hexane/EtOH = 90:10, 1.0 mL/min, τmajor = 10.60 min, τminor = 12.56 min). Absolute stereochemistry of 3ae is assigned in analogy with 3am. (R,E)-2-(tert-Butyl)-4-(4-(4-fluorophenyl)-4-oxobut2-en-1-yl)-4-hydroxy-5-methyl-2,4-dihydro-3H-pyrazol-3-one (3af). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 3af as a colorless oil (24.0 mg, 0.072 mmol, 72% yield). Rf = 0.40 (30% EtOAc in petroleum ether). FT-IR (neat): ν 3583, 3348, 2980, 2928, 2853, 2717, 2361, 1685, 1623, 1596, 1507, 1467, 1362, 1229, 1155, 1099, 1020, 971, 844 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.91-7.95 (m; 2H), 7.10-7.15 (m; 2H), 6.95 (d, J = 15.5 Hz; 1H), 6.64-6.72 (m; 1H), 4.29 (s; 1H), 2.71-2.82 (m; 2H), 2.08 (s; 3H), 1.40 (s; 9H); 13C NMR (100 MHz, CDCl3): δ 188.1, 174.6, 158.8, 139.1, 133.6, 131.24, 131.15, 129.9, 115.9, 115.7, 79.3, 57.8, 39.3, 28.0, 13.3; HRMS (ESI+): Calcd for C18H21FN2O3Na ([M + Na]+): 355.1434, found: 355.1432; [α]D22 +382.6 (c 1.00, CHCl3) for an enantiomerically enriched sample with 96:4 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IE column (254 nm, n-Hexane/EtOH = 90:10, 1.0 mL/min, τmajor = 10.03 min, τminor = 11.93 min). Absolute stereochemistry of 3af is assigned in analogy with 3am.

(R,E)-2-(tert-Butyl)-4-hydroxy-5-methyl-4-(4-oxo-4(4-(trifluoromethyl)phenyl)but-2-en-1-yl)-2,4-dihydro-3H-pyrazol-3-one (3ag). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 3ag as a colorless oil (32.0 mg, 0.084 mmol, 84% yield). Rf = 0.45 (30% EtOAc in petroleum ether). FT-IR (neat): ν 3582, 2928, 2855, 2363, 1682, 1586, 1323, 1170, 1131, 1067, 1015, 854 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.98 (d, J = 8.1 Hz; 2H), 7.72 (d, J = 8.7 Hz; 1H), 6.95 (d, J =15.1 Hz; 1H), 6.71-6.77 (m; 1H), 4.61 (s; 1H), 2.73-2.86 (m, 2H), 2.09 (s, 3H), 1.40 (s; 9H); 13C NMR (100 MHz, CDCl3): δ 189.0, 174.7, 159.0, 140.6, 140.0, 129.9, 128.8, 125.7, 125.6, 79.3, 57.8, 39.2, 28.0, 13.2; HRMS (ESI+): Calcd for C19H21F3N2O3Na ([M + Na]+): 405.1402, found: 405.1402; [α]D22 +525.4 (c 1.00, CHCl3) for an enantiomerically enriched sample with 95:5 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IE column (254 nm, n-Hexane/EtOH = 90:10, 1.0 mL/min, τmajor = 6.81 min, τminor = 7.92 min). Absolute stereochemistry of 3ag is assigned in analogy with 3am. (R,E)-4-(4-(3-Bromophenyl)-4-oxobut-2-en-1-yl)-2(tert-butyl)-4-hydroxy-5-methyl-2,4-dihydro-3H-pyrazol-3-one (3ah). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 3ah as a colorless oil (30.0 mg, 0.077 mmol, 77% yield). Rf = 0.40 (30% EtOAc in petroleum ether). FT-IR (neat): ν 3584, 3340, 2926, 2853, 1683, 1622, 1563, 1424, 1364, 1218, 1100, 1024, 971 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.03 (s; 1H), 7.81 (d, J =7.7 Hz; 1H), 7.68 (dd, J =0.8, 7.9 Hz; 1H), 7.34 (t, J =7.9 Hz; 1H), 6.93 (d, J =15.6 Hz; 1H), 6.68-6.75 (m; 1H), 4.60 (s; 1H), 2.73-2.85 (m; 2H), 2.09 (s; 3H), 1.41 (s; 9H); 13C NMR (100 MHz, CDCl3): δ 188.3, 174.7, 159.1, 140.0, 139.0, 135.8, 131.5, 130.2, 129.7, 127.0, 123.0, 79.4, 57.8, 39.2, 28.0, 13.2; HRMS (ESI+): Calcd for C18H21BrN2O3Na ([M + Na]+): 415.0633, found: 415.0630; [α]D22 +633.0 (c 1.00, CHCl3) for an enantiomerically enriched sample with 97:3 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IA column (254 nm, n-Hexane/EtOH = 90:10, 1.0 mL/min, τmajor = 11.43 min, τminor = 12.89 min). Absolute stereochemistry of 3ah is assigned in analogy with 3am. (R,E)-2-(tert-Butyl)-4-(4-(3-chlorophenyl)-4-oxobut2-en-1-yl)-4-hydroxy-5-methyl-2,4-dihydro-3H-pyrazol-3-one (3ai). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 3ai as a colorless oil (27.0 mg, 0.078 mmol, 78% yield). Rf = 0.40 (30% EtOAc in petroleum ether). FT-IR (neat): ν 3747, 3584, 2926, 2363, 1682, 1569, 1422, 1365, 1221, 1024, 861 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.877.88 (m; 1H), 7.76-7.78 (m; 1H), 7.52-7.55 (m; 1H), 7.397.43 (m; 1H), 6.93 (d, J =15.2 Hz; 1H), 6.68-6.76 (m; 1H), 4.36 (s; 1H), 2.72-2.84 (m; 2H), 2.09 (s; 3H), 1.41 (s; 9H); 13C NMR (100 MHz, CDCl3): δ 188.4, 174.6, 159.4, 140.0, 138.8, 135.0, 133.0, 130.0, 129.7, 128.6, 126.6, 79.3, 57.8, 39.2, 28.0, 13.3; HRMS (ESI+): Calcd for C18H21N2O3ClNa ([M + Na]+): 371.1138, found: 371.1140; [α]D22 +362.9 (c 1.00, CHCl3) for an enantiomerically enriched sample with 97:3 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IE column (254 nm, n-Hexane/EtOH = 90:10, 1.0 mL/min, τmajor = 10.61 min, τminor =



12.07 min). Absolute stereochemistry of 3ai is assigned in analogy with 3am. (R,E)-2-(tert-Butyl)-4-hydroxy-4-(4-(3methoxyphenyl)-4-oxobut-2-en-1-yl)-5-methyl-2,4dihydro-3H-pyrazol-3-one (3aj). Purification by silica gel (100-200 mesh) column chromatography (40% EtOAc in petroleum ether) afforded 3aj as a colorless oil (28.0 mg, 0.081 mmol, 81% yield). Rf = 0.20 (30% EtOAc in petroleum ether). FT-IR (neat): ν 3584, 3340, 2973, 2930, 1684, 1587, 1431, 1364, 1265, 1215, 1101, 1032, 974 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.43-7.47 (m; 2H), 7.34-7.38 (m; 1H), 7.11 (dd, J = 7.7 Hz; 1H), 6.96 (d, J = 15.2 Hz; 1H), 6.64-6.71 (m; 1H), 4.36 (s; 1H), 3.85 (s; 3H), 2.72-2.84 (m, 1H), 2.09 (s, 3H), 1.41 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 189.5, 174.6, 159.8, 138.9, 138.6, 130.3, 129.6, 121.2, 119.7, 112.6, 79.4, 57.8, 55.4, 39.3, 28.0, 13.3; HRMS (ESI+): Calcd for C19H24N2O4Na ([M + Na]+): 367.1634, found: 367.1631; [α]D22 +669.7 (c 1.00, CHCl3) for an enantiomerically enriched sample with 96:4 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IA column (254 nm, n-Hexane/EtOH = 90:10, 1.0 mL/min, τmajor = 16.50 min, τminor = 19.47 min). Absolute stereochemistry of 3aj is assigned in analogy with 3am. (R,E)-2-(tert-Butyl)-4-hydroxy-5-methyl-4-(4-oxo-4(o-tolyl)but-2-en-1-yl)-2,4-dihydro-3H-pyrazol-3-one (3ak). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 3ak as a colorless oil (32.0 mg, 0.076 mmol, 76% yield). Rf = 0.40 (30% EtOAc in petroleum ether). FT-IR (neat): ν 3745, 3585, 2926, 2362, 1690, 1567, 1514, 1460, 1424, 1219, 1119, 1032, 858 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.33-7.37 (m; 2H), 7.20-7.24 (m; 2H), 6.57 (d; J =15.7; 1H), 6.32-6.36 (m; 1H), 4.28 (s; 1H), 2.63-2.78 (m; 2H), 2.37 (s; 3H), 2.05 (s; 3H), 1.39 (s; 9H); 13C NMR (100 MHz, CDCl3): δ 195.5, 174.4, 158.7, 140.2, 138.0, 137.1, 134.6, 131.4, 130.7, 128.1, 125.4, 79.3, 57.7, 39.2, 27.9, 20.2, 132; HRMS (ESI+): Calcd for C19H24N2O3Na ([M + Na]+): 351.1685, found: 351.1685; [α]D22 +53.8 (c 1.00, CHCl3) for an enantiomerically enriched sample with 57:43 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IE column (254 nm, n-Hexane/EtOH = 90:10, 1.0 mL/min, τmajor = 10.61 min, τminor = 12.27 min). Absolute stereochemistry of 3ak is assigned in analogy with 3am. (R,E)-4-(4-(2-Bromophenyl)-4-oxobut-2-en-1-yl)-2(tert-butyl)-4-hydroxy-5-methyl-2,4-dihydro-3H-pyrazol-3-one (3al). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 3al as a colorless oil (33.0 mg, 0.084 mmol, 84% yield). Rf = 0.40 (30% EtOAc in petroleum ether). FT-IR (neat): ν 3745, 3325, 2926, 2362, 1686, 1621, 1428, 1364, 1219, 1023, 977 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.59 (d, J = 7.9 Hz; 1H), 7.34-7.38 (m; 1H), 7.28-7.34 (m; 2H), 6.53 (d, J = 15.7 Hz; 1H), 6.30-6.34 (m; 1H), 4.37 (s; 1H), 2.682.78 (m, 2H), 2.03 (s; 3H), 1.39 (s; 9H); 13C NMR (100 MHz, CDCl3): δ 194.0, 174.7, 158.8, 141.6, 140.3, 134.0, 133.4, 131.5, 129.0, 127.3, 119.3, 79.1, 57.7, 39.2, 28.0, 13.3; HRMS (ESI+): Calcd for C18H21BrN2O3Na ([M + Na]+): 415.0633, found: 415.0635; [α]D22 +107.6 (c 1.00, CHCl3) for an enantiomerically enriched sample with 64:36 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IE column (254 nm, n-Hexane/EtOH = 90:10, 1.0

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mL/min, τmajor = 13.61 min, τminor = 15.47 min). Absolute stereochemistry of 3al is assigned in analogy with 3am. (R,E)-2-(tert-Butyl)-4-(4-(2-chlorophenyl)-4-oxobut2-en-1-yl)-4-hydroxy-5-methyl-2,4-dihydro-3H-pyrazol-3-one (3am). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 3am as a colorless oil (28.0 mg, 0.080 mmol, 80% yield). Rf = 0.45 (30% EtOAc in petroleum ether). mp 77-78 °C (CHCl3/i-PrOH/Et2O). FT-IR (neat): ν 3583, 3338, 2928, 2854, 1683, 1623, 1432, 1364, 1218, 1031, 977 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.29-7.42 (m; 4H), 6.56 (d, J = 15.6 Hz; 1H), 6.31-6.39 (m; 1H), 4.47 (s; 1H), 2.68-2.79 (m; 2H), 2.03 (s; 3H), 1.38 (s; 9H); 13C NMR (100 MHz, CDCl3): δ 193.1, 174.6, 158.9, 141.1, 138.2, 134.1, 131.5, 131.2, 130.3, 129.1, 126.8, 79.1, 57.8, 39.2, 27.9, 13.2; HRMS (ESI+): Calcd for C18H21N2O3ClNa ([M + Na]+): 371.1138, found: 371.1140; [α]D22 +803.6 (c 1.00, CHCl3) for an enantiomerically enriched sample with >99:1 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IA column (254 nm, n-Hexane/EtOH = 90:10, 1.0 mL/min, τmajor = 8.06 min, τminor = 11.17 min) and found to be 79:21. Absolute stereochemistry of 3am is determined by single crystal Xray diffraction analysis. (R,E)-2-(tert-Butyl)-4-(4-(2,4-dimethoxyphenyl)-4oxobut-2-en-1-yl)-4-hydroxy-5-methyl-2,4-dihydro3H-pyrazol-3-one (3an). Purification by silica gel (100200 mesh) column chromatography (40% EtOAc in petroleum ether) afforded 3an as a colorless oil (26.0 mg, 0.070 mmol, 70% yield). Rf = 0.25 (30% EtOAc in petroleum ether). FT-IR (neat): ν 3748, 3331, 2926, 1690, 1604, 1462, 1420, 1258, 1213, 1163, 1127, 1026, 973 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 8.6 Hz; 1H), 6.94 (d, J = 15.4 Hz; 1H), 6.47-6.55 (m; 2H), 6.44 (d, J = 2.1 Hz; 1H), 3.86 (s; 3H), 3.85 (s; 3H), 2.70 (d, J = 7.4 Hz; 2H), 2.07 (s, 3H), 1.41 (s; 9H); 13C NMR (100 MHz, CDCl3): δ 189.6, 174.6, 164.4, 160.5, 135.3, 135.1, 132.9, 121.3, 105.2, 98.4, 79.3, 57.7, 55.5, 39.2, 28.0, 13.3; HRMS (ESI+): Calcd for C20H26N2O5Na ([M + Na]+): 397.1739, found: 397.1735; [α]D22 +132.1 (c 1.00, CHCl3) for an enantiomerically enriched sample with 89:11 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IE column (254 nm, n-Hexane/EtOH = 85:15, 1.0 mL/min, τmajor = 21.57 min, τminor = 24.51 min). Absolute stereochemistry of 3an is assigned in analogy with 3am. (R,E)-2-(tert-Butyl)-4-(4-(2,4-dichlorophenyl)-4-oxobut-2-en-1-yl)-4-hydroxy-5-methyl-2,4-dihydro-3Hpyrazol-3-one (3ao). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 3ao as a colorless oil (30.0 mg, 0.078 mmol, 78% yield). Rf = 0.45 (30% EtOAc in petroleum ether). FT-IR (neat): ν 3563, 2928, 2884, 1671, 1620, 1367, 1208, 1038, 874 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.43 (s; 1H), 7.31 (s; 2H), 6.56 (d, J = 15.8 Hz; 1H), 6.38-6.44 (m; 1H), 4.56 (s; 1H), 2.67-2.78 (m; 2H), 2.04 (s; 3H), 1.40 (s; 9H); 13C NMR (100 MHz, CDCl3): δ 191.7, 174.7, 159.0, 141.4, 137.1, 136.6, 133.7, 132.3, 130.3, 130.2, 127.2, 79.3, 57.8, 39.1, 27.9, 13.2; HRMS (ESI+): Calcd for C18H20Cl2N2O3Na ([M + Na]+): 405.0749, found: 405.0746; [α]D22 +76.6 (c 1.00, CHCl3) for an enantiomerically enriched sample with 64:36 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IA column (254 nm, n-Hexane/EtOH =


Page 7 of 12 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


85:15, 1.0 mL/min, τmajor = 7.00 min, τminor = 8.71 min). Absolute stereochemistry of 3ao is assigned in analogy with 3am. (R,E)-2-(tert-Butyl)-4-(4-(3,4-dichlorophenyl)-4-oxobut-2-en-1-yl)-4-hydroxy-5-methyl-2,4-dihydro-3Hpyrazol-3-one (3ap). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 3ap as a colorless oil (31.0 mg, 0.081 mmol, 81% yield). Rf = 0.40 (30% EtOAc in petroleum ether). FT-IR (neat): ν 3583, 3343, 2928, 2854, 1681, 1624, 1367, 1218, 1028, 974 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 1.7 Hz; 1H), 7.73 (dd, J = 1.4, 8.3 Hz; 1H), 7.55 (d, J = 8.3 Hz; 1H), 6.92 (d, J = 15.6 Hz; 1H), 6.70-6.78 (m; 1H), 4.26 (s; 1H), 2.71-2.83 (m; 2H), 2.09 (s; 3H), 1.41 (s; 9H); 13C NMR (100 MHz, CDCl3): δ 187.3, 174.5, 158.8, 140.4, 137.6, 136.8, 133.4, 130.8, 130.5, 129.3, 127.5, 79.2, 57.8, 39.2, 28.0, 13.3; HRMS (ESI+): Calcd for C18H20Cl2N2O3Na ([M + Na]+): 405.0749, found: 405.0750; [α]D22 +206.5 (c 1.00, CHCl3) for an enantiomerically enriched sample with 97:3 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IE column (254 nm, n-Hexane/EtOH = 90:10, 1.0 mL/min, τmajor = 9.20 min, τminor = 10.05 min). Absolute stereochemistry of 3ap is assigned in analogy with 3am. (R,E)-2-(tert-Butyl)-4-hydroxy-5-methyl-4-(4-(naphthalen-1-yl)-4-oxobut-2-en-1-yl)-2,4-dihydro-3H-pyrazol-3-one (3aq). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 3aq as a colorless oil (30.0 mg, 0.082 mmol, 82% yield). Rf = 0.45 (30% EtOAc in petroleum ether). FT-IR (neat): ν 3584, 3367, 2925, 1717, 1621, 1595, 1497, 1364, 1276, 1223, 1128, 1014, 976, 898 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.25 (d, J = 7.7 Hz; 1H), 7.96 (d, J = 8.2 Hz; 1H), 7.86-7.88 (m, 1H), 7.64 (d, J = 7.0 Hz; 1H), 7.45-7.57 (m; 3H), 6.74 (d, J = 15.6 Hz; 1H), 6.45-6.53 (m, 1H), 4.73 (s; 1H), 2.69-2.82 (m; 2H), 2.05 (s; 3H), 1.35 (s; 9H); 13C NMR (100 MHz, CDCl3): δ 194.6, 178.4, 159.4, 140.2, 135.9, 134.9, 133.8, 132.0, 130.4, 128.4, 127.5, 126.5, 125.4, 124.3, 79.4, 57.7, 39.2, 27.9, 13.2; HRMS (ESI+): Calcd for C22H24N2O3Na ([M + Na]+): 387.1685, found: 387.1684; [α]D22 +20.3 (c 1.00, CHCl3) for an enantiomerically enriched sample with 59:41 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IE column (254 nm, n-Hexane/EtOH = 85:15, 1.0 mL/min, τmajor = 11.53 min, τminor = 15.33 min). Absolute stereochemistry of 3aq is assigned in analogy with 3am. (R,E)-2-(tert-Butyl)-4-hydroxy-5-methyl-4-(4-oxo-4(thiophen-2-yl)but-2-en-1-yl)-2,4-dihydro-3H-pyrazol3-one (3ar). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 3ar as a colorless oil (28.0 mg, 0.087 mmol, 87% yield). Rf = 0.30 (30% EtOAc in petroleum ether). FT-IR (neat): ν 3367, 2928, 1710, 1629, 1585, 1490, 1362, 1276, 1223, 1128, 1012, 976, 878 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 3.8 Hz; 1H), 7.67 (dd, J = 0.7, 5.0 Hz; 1H), 7.137.15 (m; 1H), 6.89 (d, J = 15.4 Hz; 1H), 6.69-6.77 (m; 1H), 4.57 (s; 1H), 2.72-2.83 (m; 2H), 2.08 (s; 3H), 1.41 (s; 9H); 13C NMR (100 MHz, CDCl3): δ 181.4, 174.7, 159.1, 144.6, 138.2, 134.3, 132.4, 129.8, 128.3, 79.4, 57.8, 39.1, 28.0, 13.3; HRMS (ESI+): Calcd for C16H20N2O3SNa ([M + Na]+): 343.1092,

found: 343.1090; [α]D22 +214.6 (c 1.00, CHCl3) for an enantiomerically enriched sample with 91:9 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IE column (254 nm, n-Hexane/EtOH = 90:10, 1.0 mL/min, τmajor = 17.29 min, τminor = 19.16 min). Absolute stereochemistry of 3ar is assigned in analogy with 3am. (R,E)-4-(4-(Benzo[d][1,3]dioxol-5-yl)-4-oxobut-2-en-1yl)-2-(tert-Butyl)-4-hydroxy-5-methyl-2,4-dihydro-3Hpyrazol-3-one (3as). Purification by silica gel (100-200 mesh) column chromatography (35% EtOAc in petroleum ether) afforded 3as as a colorless oil (28.0 mg, 0.078 mmol, 78% yield). Rf = 0.30 (30% EtOAc in petroleum ether). FT-IR (neat): ν 3544, 3267, 2925, 1717, 1618, 1590, 1497, 1364, 1276, 1213, 1128, 1024, 970, 878 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.51 (dd, J = 1.6, 8.2 Hz; 1H), 7.41 (d, J =1.6 Hz; 1H), 6.93 (d, J = 15.3 Hz; 1H), 6.84 (d, J = 8.2 Hz; 1H), 6.60-6.68 (m; 1H), 6.04 (s; 2H), 4.52 (s; 1H), 2.71-2.82 (m; 2H), 2.08 (s; 3H), 1.40 (s; 9H); 13C NMR (100 MHz, CDCl3): δ 187.5, 174.7, 158.9, 151.9, 148.3, 138.1, 132.0, 130.0, 125.0, 108.3,107.9, 101.9, 79.4, 57.7, 39.2, 28.0, 13.2; HRMS (ESI+): Calcd for C19H22N2O5Na ([M + Na]+): 381.1426, found: 381.1424; [α]D22 +315.1 (c 1.00, CHCl3) for an enantiomerically enriched sample with 95.5:4.5 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IE column (254 nm, n-Hexane/EtOH = 90:10, 1.0 mL/min, τmajor = 12.29 min, τminor = 13.48 min). Absolute stereochemistry of 3as is assigned in analogy with 3am. (R,E)-2-(tert-Butyl)-4-hydroxy-5-methyl-4-(4-oxo-6phenylhex-2-en-1-yl)-2,4-dihydro-3H-pyrazol-3-one (3at). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 3at as a colorless oil (27.0 mg, 0.079 mmol, 79% yield). Rf = 0.35 (30% EtOAc in petroleum ether). FT-IR (neat): ν 3346, 2929, 1689, 1631, 1551, 1451, 1364, 1219, 1098, 1022, 978 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.26-7.29 (m; 2H), 7.167.20 (m; 3H), 6.47-6.54 (m; 1H), 6.16 (d, J = 15.8 Hz; 1H), 4.24 (s; 1H), 2.89-2.93 (m; 2H), 2.80-2.85 (m; 2H), 2.58-2.65 (m, 2H), 2.02 (s, 3H), 1.42 (s; 9H); 13C NMR (100 MHz, CDCl3): δ 198.5, 174.6, 158.1, 140.9, 137.1, 134.2, 128.5, 128.3, 126.1, 79.1, 57.7, 41.8, 38.9, 29.7, 28.0, 13.2; HRMS (ESI+): Calcd for C20H26N2O3Na ([M + Na]+): 365.1841, found: 365.1844; [α]D22 +110.3 (c 1.00, CHCl3) for an enantiomerically enriched sample with 83:17 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IE column (254 nm, n-Hexane/EtOH = 90:10, 1.0 mL/min, τmajor = 8.23 min, τminor = 8.83 min). Absolute stereochemistry of 3at is assigned in analogy with 3am. (R,E)-2-(tert-Butyl)-4-(4-cyclohexyl-4-oxobut-2-en1-yl)-4-hydroxy-5-methyl-2,4-dihydro-3H-pyrazol-3one (3au). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 3au as a colorless oil (25.0 mg, 0.078 mmol, 78% yield). Rf = 0.45 (30% EtOAc in petroleum ether). FT-IR (neat): ν 3580, 3357, 2924, 1717, 1621, 1595, 1497, 1374, 1296, 1223, 1028, 1014, 976, 878 cm−1; 1H NMR (400 MHz, CDCl3): δ 6.43-6.51 (m; 1H), 6.22 (d, J = 15.7 Hz; 1H), 4.40 (s; 1H), 2.63-2.68 (m; 2H), 2.47-2.51 (m; 1H), 2.04 (s; 3H), 1.77 (d, J = 9.7 Hz; 4H), 1.43 (s; 9H), 1.23-1.32 (m; 6H); 13C NMR (100 MHz, CDCl3): δ 202.4, 174.7, 159.4, 136.3, 132.9, 79.3, 57.8, 48.6, 39.0, 28.5, 28.4, 28.0, 25.8, 25.64, 25.59, 13.2; HRMS (ESI+): Calcd for C18H28N2O3Na ([M + Na]+): 343.1998,



found: 343.1999; [α]D22 +142.8 (c 1.00, CHCl3) for an enantiomerically enriched sample with 86:14 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IE column (254 nm, n-Hexane/EtOH = 85:15, 1.0 mL/min, τmajor = 7.49 min, τminor = 8.18 min). Absolute stereochemistry of 3au is assigned in analogy with 3am. (R,E)-5-(tert-Butyl)-4-hydroxy-4-(4-oxo-4-phenylbut-2-en-1-yl)-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (3ba). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 3ba as a colorless oil (29.0 mg, 0.077 mmol, 77% yield). Rf = 0.45 (30% EtOAc in petroleum ether). FT-IR (neat): ν 3373, 2970, 2869, 2337, 1719, 1596, 1497, 1373, 1277, 1221, 1126, 978, 962, 893, 848 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.77-7.83 (m; 2H), 7.70 (d, J = 7.3 Hz; 2H), 7.457.48 (m; 1H), 7.26-7.35 (m, 4H), 7.14 (q, J = 7.3 Hz; 1H), 6.84 (d, J = 15.4; 1H), 6.56-6.63 (m; 1H), 4.12 (s; 1H), 2.98-3.11 (m; 2H), 1.42 (m; 9H); 13C NMR (100 MHz, CDCl3): δ 190.6, 138.2, 137.2, 137.0, 132.8, 131.3, 128.84, 128.80, 128.6, 128.4, 125.4, 118.9, 118.8, 81.8, 41.2, 36.4, 28.7; HRMS (ESI+): Calcd for C23H24N2O3Na ([M + Na]+): 399.1685, found: 399.1683; HRMS (ESI+): Calcd for C23H24N2O3Na ([M + Na]+): 399.1685, found: 399.1683; [α]D22 +454.2 (c 1.00, CHCl3) for an enantiomerically enriched sample with 77:23 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IE column (254 nm, n-Hexane/EtOH = 90:10, 1.0 mL/min, τmajor = 11.65 min, τminor = 12.61 min). Absolute stereochemistry of 3ba is assigned in analogy with 3am. (R,E)-4-Hydroxy-5-methyl-4-(4-oxo-4-phenylbut-2en-1-yl)-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (3ca). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 3ca as a colorless oil (25.0 mg, 0.075 mmol, 75% yield). Rf = 0.45 (30% EtOAc in petroleum ether). FT-IR (neat): ν 3584, 3367, 2925, 1717, 1621, 1595, 1497, 1364, 1276, 1223, 1128, 1014, 976, 898 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.75-7.83 (m; 4H), 7.48-7.51 (m; 1H), 7.30-7.37 (m; 4H), 7.14-7.18 (m; 1H), 6.92 (d, J = 15.5 Hz; 1H), 6.70-6.78 (m, 1H), 4.51 (s; 1H), 2.81-2.93 (m, 2H), 2.20 (s; 3H); 13C NMR (100 MHz, CDCl3): δ 190.5, 172.9, 161.5, 138.3, 137.2, 137.0, 133.0, 131.2, 128.9, 128.6, 128.5, 125.5, 118.9, 79.4, 39.2, 13.4; HRMS (ESI+): Calcd for C20H18N2O3Na ([M + Na]+): 357.1215, found: 357.1211; [α]D22 +119.2 (c 1.00, CHCl3) for an enantiomerically enriched sample with 89:11 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IE column (254 nm, n-Hexane/EtOH = 90:10, 1.0 mL/min, τmajor = 24.30 min, τminor = 26.06 min). Absolute stereochemistry of 3ca is assigned in analogy with 3am. (R,E)-4-Hydroxy-4-(4-oxo-4-phenylbut-2-en-1-yl)2,5-diphenyl-2,4-dihydro-3H-pyrazol-3-one (3da). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 3da as a colorless oil (34.0 mg, 0.086 mmol, 86% yield). Rf = 0.45 (30% EtOAc in petroleum ether). FT-IR (neat): ν 3583, 3362, 3061, 1721, 1624, 1594, 1494, 1448, 1281, 1215, 1137, 1097, 1018, 980, 948, 893 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.11-8.13 (m; 2H), 7.88 (d, J =8.3 Hz; 2H), 7.64 (d, J =7.8 Hz; 2H), 7.44-7.48 (m; 4H), 7.35 (t, J = 7.8 Hz; 2H), 7.25-7.29 (m; 2H), 7.19 (t, J =7.2 Hz; 1H), 6.70 (d, J = 15.8 Hz;

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1H), 6.52-6.59 (m; 1H), 4.64 (s; 1H), 3.00-3.11 (m; 2H); 13C NMR (100 MHz, CDCl3): δ 190.6, 173.4, 158.0, 137.8, 137.2, 136.9, 132.8, 131.6, 131.1, 129.3, 128.9, 128.6, 128.4, 127.0, 125.8, 119.1, 80.2, 41.1; HRMS (ESI+): Calcd for C25H20N2O3Na ([M + Na]+): 419.1372, found: 419.1370; [α]D22 +101.6 (c 1.00, CHCl3) for an enantiomerically enriched sample with 80:20 er. The enantiomeric ratio was determined by HPLC analysis using Phenomenex Cellulose1 column (254 nm, n-Hexane/EtOH = 85:15, 1.0 mL/min, τmajor = 9.63 min, τminor = 11.00 min). Absolute stereochemistry of 3da is assigned in analogy with 3am. (R,E)-2-Benzyl-4-hydroxy-5-methyl-4-(4-oxo-4-phenylbut-2-en-1-yl)-2,4-dihydro-3H-pyrazol-3-one (3ea). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 3ea as a colorless oil (26.0 mg, 0.075 mmol, 75% yield). Rf = 0.45 (10% EtOAc in petroleum ether. FT-IR (neat): ν 3584, 3340, 2924, 2362, 1701, 1620, 1440, 1270, 1227, 1108, 1077, 1023, 982 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.86-7.88 (m; 2H), 7.56 (t, J = 7.2 Hz; 1H), 7.44 (t, J = 7.8 Hz; 1H), 7.16-7.20 (m; 5H), 6.98 (d, J = 15.5 Hz; 1H), 6.68-6.76 (m; 1H), 4.744.84 (m; 2H), 4.62-4.67 (m; 1H), 2.77-2.90 (m; 2H), 2.10 (s; 3H); 13C NMR (100 MHz, CDCl3): δ 189.6, 174.4, 138.3, 137.1, 135.5, 133.0, 130.6, 128.64, 128.61,128.59, 127.8, 127.7, 78.3, 48.0, 38.8, 13.2; HRMS (ESI+): Calcd for C21H20N2O3Na ([M + Na]+): 371.1372, found: 371.1371; [α]D22 +146.5 (c 1.00, CHCl3) for an enantiomerically enriched sample with 80:20 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IE column (254 nm, n-Hexane/EtOH = 90:10, 1.0 mL/min, τmajor = 18.79 min, τminor = 22.55 min). Absolute stereochemistry of 3ea is assigned in analogy with 3am. Procedure for the Hydrogenation of 3aa to 4. To a solution of 3aa (25.0 mg, 0.080 mmol, 1.0 equiv) in MeOH (3.0 mL), 5% Pd-C (1.3 mg, 0.004 mmol, 0.05 equiv) was added. The resulting mixture was degassed and stirred under H 2 balloon pressure for 5 h at 25 °C. The reaction mixture was filtered over Celite®. The filtrate was concentrated under reduced pressure to obtain an oil. (R)-2-(tert-Butyl)-4-hydroxy-5-methyl-4-(4-oxo-4phenylbutyl)-2,4-dihydro-3H-pyrazol-3-one (4). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 4 as a colorless oil (23.0 mg, 0.07 mmol, 92% yield). Rf = 0.40 (30% EtOAc in petroleum ether. FT-IR (neat): ν 3337, 2926, 2383, 1688, 1365, 1210, 1026, 969 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.91-7.93 (m; 2H), 7.54-7.58 (m; 1H), 7.44-7.47 (m; 2H), 3.11 (s; 1H), 2.97-3.01 (m; 2H), 2.09 (s; 3H), 1.801.85 (m; 2H), 1.53-1.65 (m; 2H), 1.48 (s; 9H); 13C NMR (100 MHz, CDCl3): δ 199.1, 175.4, 159.7, 136.7, 133.1, 128.6, 127.9, 79.7, 57.5, 37.7, 35.3, 28.1, 16.8, 13.1; HRMS (ESI+): Calcd for C18H24N2O3Na ([M + Na]+): 339.1685, found: 339.1683; [α]D22 +330.5 (c 1.00, CHCl3) for an enantiomerically enriched sample with 96:4 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IB column (254 nm, n-Hexane/EtOH = 85:15, 1.0 mL/min, τmajor = 4.93 min, τminor = 5.37 min). Procedure for the Hydrogenation of 3aa to 5. To a solution of 3aa (25.0 mg, 0.080 mmol, 1.0 equiv) in MeOH (3.0 mL), 15% Pd-C (3.8 mg, 0.012 mmol, 0.15 equiv) was added. The resulting mixture was degassed and stirred under H 2


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balloon pressure for 48 h at 25 °C. The reaction mixture was filtered over Celite®. The filtrate was concentrated under reduced pressure to obtain an oil. The diastereomeric ratio (dr) was determined from the 1H NMR of the crude reaction mixture and found to be >20:1. (4R)-2-(tert-Butyl)-4-hydroxy-4-(4-hydroxy-4-phenylbutyl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one (5). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 5 as a colorless oil (24.2 mg, 0.076 mmol, 95% yield). Rf = 0.40 (30% EtOAc in petroleum ether. FT-IR (neat): ν 3370, 2928, 2362, 1688, 1364, 1216, 1100, 1023 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.25-7.34 (m; 5H), 4.61-4.67 (m; 1H), 3.94 (s; 1H), 1.97 (s; 3H), 1.61-1.91 (m; 4H), 1.42 (d, J = 3.0 Hz; 9H), 1.14-1.24 (m; 2H); 13C NMR (100 MHz, CDCl3): δ 175.3, 159.4, 144.4, 128.5, 127.64, 127.59, 125.74, 125.69, 79.7, 73.8, 57.5, 38.6, 35.7, 28.0, 18.8, 13.0; HRMS (ESI+): Calcd for C18H26N2O3Na ([M + Na]+): 341.1841, found: 341.1841; [α]D22 +300.9 (c 1.00, CHCl3) for an enantiomerically enriched sample with 96:4 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak ADH column (254 nm, n-Hexane/EtOH = 85:15, 1.0 mL/min, τmajor = 9.10 min, τminor = 14.64 min). Procedure for the Epoxidation of 3aa. In a 5mL round bottom flask, 3aa (25.0 mg, 0.080 mmol, 1.0 equiv) was taken in acetone/20% aq Na2CO3 (1:1, 1 mL). To this solution, was added aq H2O2 (30% v/v) and the resulting solution was stirred for 2 h at 0 °C followed by 1.5 h at 25 °C. The reaction mixture was diluted with CH2Cl2 and water. The organic phase was separated from the aqueous phase. The aqueous phase was extracted with additional CH2Cl2. The combined organic phase was dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain a sticky liquid. The diastereomeric ratio (dr) was determined from the 1H NMR of the crude reaction mixture and found to be 1.7:1. (4R)-4-((3-Benzoyloxiran-2-yl)methyl)-2-(tert-butyl)-4-hydroxy-5-methyl-2,4-dihydro-3H-pyrazol-3one (6). Purification by silica gel (100-200 mesh) column chromatography (30% EtOAc in petroleum ether) afforded 6 as a colorless oil (28.0 mg, 0.080 mmol, >99% yield). Rf = 0.40 (30% EtOAc in petroleum ether. FT-IR (neat): ν 3370, 1916, 1362, 1689, 1450, 1362, 1233, 1100, 916 cm −1; 1H NMR (400 MHz, CDCl3): Signals corresponding to the major diastereomer: δ 8.00-8.04 (m; 3H), 7.59-7.62 (m; 1H), 7.467.50 (m; 3H), 4.37 (s; 1H), 4.05-4.06 (m; 1H), 2.98-3.01 (m; 1H), 2.23-2.30 (m; 1H), 2.10 (s; 3H), 1.36 (s; 9H); 13C NMR (100 MHz, CDCl3): δ 193.9, 193.6, 175.1, 174.6, 159.6, 135.3, 134.03, 133.99, 128.81, 128.78, 128.5, 128.4, 78.2, 57.9, 57.7, 56.36, 56.30, 54.0, 38.3, 33.8, 27.9, 24.9, 13.5, 13.1; HRMS (ESI+): Calcd for C18H22N2O4Na ([M + Na]+): 353.1477, found: 353.1479. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak ADH column (254 nm, n-Hexane/EtOH = 85:15, 1.0 mL/min, τmajor = 10.17 min, τminor = 11.37 min for the major diastereomer and τ major = 13.02 min, τminor = 19.52 min for the minor diastereomer) and found to be 96:4 for both the diastereomers.

Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.xxxxxxxx.

Copies of 1H and 13C NMR spectra of products, HPLC spectra of products, and X-ray crystallographic data (ORTEP) of 3am (PDF) CCDC 1850756 contains 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.

*E-mail: [email protected] Bidisha Ray: 0000-0002-4397-7044 Santanu Mukherjee: 0000-0001-9651-6228 The authors declare no competing financial interest.

This research is funded by Science and Engineering Research Board (SERB), New Delhi [Grant No. EMR/2016/005045]. B.R. thanks IISc Bangalore for a doctoral fellowship. We thank Dr. Soumya Jyoti Singha Roy for helpful discussion. We wish to thank Mr. Prodip Howlader (Department of Inorganic and Physical Chemistry, IISc, Bangalore) for his help with the X-ray diffraction analysis.

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Direct Catalytic Enantioselective Vinylogous Aldol Reaction of Allyl

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