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Cite This: J. Org. Chem. 2019, 84, 1053−1063

Pyrrolidine-Oxadiazolone Conjugates as Organocatalysts in Asymmetric Michael Reaction Chandan K. Mahato,†,‡ Sayan Mukherjee,‡ Mrinalkanti Kundu,*,† and Animesh Pramanik*,‡ †

TCG Lifesciences Pvt. Ltd., BN-7, Salt Lake City, Kolkata 700091, India Department of Chemistry, University of Calcutta, 92, A. P. C. Road, Kolkata 700009, India

‡

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S Supporting Information *

ABSTRACT: Pyrrolidine-oxadiazolone based organocatalysts are envisaged, synthesized, and utilized for asymmetric Michael reactions. Results of the investigations suggest that some of the catalysts are indeed efficient for stereoselective 1,4-conjugated Michael additions (dr: >97:3, ee up to 99%) in high chemical yields (up to 97%) often in short reaction time. As an extension, one enantiopure Michael adduct has been utilized to synthesize optically active octahydroindole.

M

extensively as asymmetric organocatalyst, and they accelerate the range of transformations such as Michael addition, aldol, or Mannich reaction. Both the enantiomeric forms of proline are inexpensive and have an amine and a carboxylic acid as functional groups. In effect, proline can function as bifunctional asymmetric catalyst and thereby became successful for facilitating stereoselective chemical transformations similar to enzymatic catalysis. Thus, the use of proline and the small molecules derived from it has been a major breakthrough in the field of organocatalysis to synthesize compounds with improved stereoselectivities.11−21 Typically, the 1,4-Michael additions with proline as organocatalyst afford modest enantioselectivity; surprisingly though, homoproline is found to be ineffective.11a,14c Both proline and homoproline are bipolar molecules; the reactions usually require polar solvents like DMSO or alcohol because of their insoluble nature. The oxadiazolone ring is frequently employed as a bioisostere for a carboxylic acid for having similar pKa. Considering that this group is nonionic and thus might improve the solubility in different organic solvents in general, we envisaged to synthesize proline-oxadiazolone conjugates and examined their effect as new organocatalysts in asymmetric Michael addition reactions. To test our hypothesis, compound 1 (Figure 1) was synthesized starting from corresponding cyanopyrrolidine following literature procedure.22 The synthesis of new chiral catalyst 2 (Scheme 1) and its opposite isomer 8 were done

olecular chirality shows immense importance in the modern pharmaceutical industry. It is widely known in the literature that biological activity, pharmacokinetics, and toxicity of enantiomers differ significantly.1 As an example, the case of thalidomide,2 whose enantiomers differ dangerously in pharmacological effect, emphasizes the importance of addressing stereochemistry in drug development. Usually, one particular optically active form of enantiomer is predominant in nature. Similarly, for synthetic chiral drug substances, since one of the enantiomers demonstrates the desired physiological effect, it is desirable to identify new synthetic methodology for specific enantiomers. In asymmetric synthesis, however, the formation of the multiple stereocenters in one reaction has been a challenging task.3 The asymmetric Michael reactions are universally acknowledged as one of the most important C−C bond-forming reactions in organic synthesis.4 Stereoselective Michael addition is thus considered for the assessment of the performance of newly designed catalysts5 as various biologically active substances contain these types of 1,4conjugated adducts with multiple stereogenic centers as their core scaffolds.6 To date, various reagent systems mostly based on metal catalysts7 are used for these types of transformation. On the other hand, for environment-benign nonmetal-catalyzed asymmetric synthesis, substantial attention has also been paid to develop efficient small-molecule chiral organocatalysts.8−10 This field of research has thus seen remarkable progress in the past few years through a large number of contributions, including the development of new organocatalyst designs. In this context the proline based molecules have been exploited © 2018 American Chemical Society

Received: September 29, 2018 Published: December 21, 2018 1053

DOI: 10.1021/acs.joc.8b02393 J. Org. Chem. 2019, 84, 1053−1063

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The Journal of Organic Chemistry

Scheme 2. Asymmetric Organocatalysis in Michael Reaction

Figure 1. (a) Pyrrolidine-oxadiazolone catalysts 1 and 2. (b) Proposed transition state.

Table 1. Effect of the Two Catalysts in Michael Addition Reactiona

using L- and D-prolines Ia and Ib, respectively. Accordingly, Ia and Ib were converted to N-Bocprolinols IIIa and IIIb via prolinol intermediates IIa and IIb. O-Tosyl intermediates IVa and IVb were synthesized using p-toluenesulfonyl chloride in dichloromethane in the presence of triethyl amine.16,23 The tosyl derivatives IVa and IVb were then converted to cyano derivatives Va and Vb using NaCN in DMSO, which were then transformed into VIIa and VIIb, respectively.22 Finally, BOC-group was removed by 4.0 M HCl in 1,4-dioxane, and the crude compounds were triturated with diethyl ether and dried to give pure 2 and 8. Initial investigations were performed on two model reactions in parallel using nitrostyrene 3a and cyclohexanone 4 as Michael acceptor and donor respectively (Scheme 2). The reactions were done using 10 mol % catalyst under neat condition at room temperature, which resulted in the desired 1,4-addition product 5a in excellent yields in short reaction time (Table 1). Catalyst 1 gave low stereoselectivity, whereas catalyst 2, to our delight, was extremely efficient in achieving high diastereo- and enantioselectivity, probably suggesting that the introduction of a flexible methylene linker is crucial for attaining ideal transition state geometry (Figure 1b) where an electrostatic interaction between the nitrogen of the pyrrolidine ring and the nitro group including an extended hydrogen-bonding can be proposed in line with literature precedence.14c,24 In going forward, we then picked catalyst 2, and various solvents were screened to optimize the reaction condition (Table 2). Results in Table 2 show that the catalyst 2 was found to be efficient indeed in a wide range of solvents such as DMSO, THF, DCE, CHCl3, and 2-propanol, though the yields and

entry

catalyst

time (h)

% yieldb

syn/antic (dr)

eed (%)

1 2

1 2

8 6

84 72

− 93:7

29 98

a

Reactions were carried out using nitrostyrene 3a (1 equiv), cyclohexanone 4 (5 mol equiv), catalyst 1/2 (10 mol %), TEA (10 mol %) in neat condition at room temp. bIsolated yields. GC−MS of reaction mixture indicated full conversion of reactants. cDiastereomeric ratio (dr) was calculated from the 1H NMR of the crude product. dEnantiomeric excess (ee, corresponds to syn-isomer) was determined by chiral HPLC.

Table 2. Role of Different Solvents in Michael Addition Using Catalyst 2a entry

solvent

time (h)

% yieldb

syn/antic (dr)

eed (%)

1 2 3 4 5 6 7 8

DMSO Neat THF DCE CHCl3 Absolute EtOH 2-Propanol Water

24 6 24 16 16 4 6 28

61 72 68 78 72 82 65 20

>97:3 93:7 95:5 93:7 92:8 >97:3 92:8 −

75 98 89 97 94 98 93 −

a

Reactions were carried out using nitrostyrene 3a (1 equiv), cyclohexanone 4 (5 mol equiv), catalyst 2 (10 mol %), TEA (10 mol %) in neat or solvent at RT. bIsolated yields. cDiastereomeric ratio (dr) was calculated from the 1H NMR of the crude product, dr >97:3, syn-isomer is major. dChiral HPLC was used to determine enantiomeric excess (ee), corresponds to syn-isomer.

Scheme 1. Synthesis of Organocatalyst 2 and 8

1054

DOI: 10.1021/acs.joc.8b02393 J. Org. Chem. 2019, 84, 1053−1063

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The Journal of Organic Chemistry enantioselectivities differ in comparison to the reaction conducted under neat condition (entries 1−5, 7). Among these, except 2-propanol, reactions in other solvents (entries 1, 3−5) were relatively sluggish. It is worth noting that the reaction in absolute ethanol gave us the best result with respect to yield as well as both diastereo- and enantioselectivity. Moreover, the duration of the reaction was reasonably short (entry 6). Pleasingly, our results demonstrate significant improvement over the data reported for both proline11a,14c and homoproline.14c The use of more polar solvent water was detrimental (entry 8; due to meager chemical yield % ee and syn/anti ratio were not determined). Having optimized the solvent as absolute EtOH for our reaction, the Michael addition of 4 to 3a was planned using different catalyst loading. Table 3 shows that the reaction with 5 mol % catalyst loading was low yielding and less enantioselective, that led us to employ 10 mol % of catalyst in our subsequent experiments.

Table 4. Stereoselective 1,4-Conjugated Addition of Cyclohexanone to Nitrostyrenes Using Catalyst 2a,b

Table 3. Effect of Catalyst 2 Concentrationa entry

catalyst (mol %)

TEA (mol %)

time (h)

% yieldb

syn/antic (dr)

eed (%)

1 2

10 5

10 5

4 24

82 30

>97:3 >97:3

98 87

a

Reactions were carried out using nitrostyrene 3a (1 equiv), cyclohexanone 4 (5 mol equiv) in absolute EtOH at room temp. b Isolated yields. cDiastereomeric ratio (dr) was calculated from the 1 H NMR of the crude product, dr >97:3, syn-isomer is major. dChiral HPLC was used to determine enantiomeric excess (ee), corresponds to syn-isomer. a

Reactions were carried out using nitrostyrene (1 equiv), cyclohexanone (5 equiv), catalyst 2 (10 mol %), TEA (10 mol %), absolute EtOH, RT. bIsolated yields, dr determined by the 1H NMR of the crude product, dr >97:3, syn-isomer is major; chiral HPLC was used to determine enantiomeric excess (ee), corresponds to the syn-isomer.

Once we established the optimal reaction condition from all the above experiments, we investigated the substrate scope for the 1,4-Michael addition reactions using various nitroolefins as acceptors and cyclohexanone 4 as donor in the presence of 10 mol % catalyst 2. The results are summarized in Table 4. Table 4 shows that the new organocatalyst 2 is also efficient for other nitrostyrenes bearing both electron donating and withdrawing group/s. The corresponding Michael adducts (5b−g) were obtained in high yields and having very good enantioselectivity where 5e was found to be the best. Nitroolefins containing naphthyl group and heteroaryl groups were equally efficient in terms of both chemical yield and stereoselectivity, providing desired adducts 5h−k. Interestingly, nonaromatic Michael acceptor such as 3l was also consistent with the formation of 5l in high diastereo- and enantioselectivity. Encouraged by these findings, 1,4-conjugated additions between other easily available ketones and aldehydes as donors and 3a as the Michael acceptor were attempted next (Table 5). From this study we observed that, among the different ketones, pyran-4-one and thiopyran-4-one were more suitable affording products 7a and 7b in short reaction time with high diastereo- and enantioselectivity. As expected, 2-butanone resulted in regioisomeric products 7c and 7d with low to moderate enantioselectivity. Use of acetone was nonbeneficial with respect to reaction time and enantioselectivity albeit high yield of the Michael adduct 7e. 3-Pentanone afforded meager conversion to 7f. When propanaldehyde was used as Michael donor, it rendered moderate yield and diastereoselectivity for 7g, whereas the enantioselectivity was found to be 46%. It is

worth to note that the reaction was very slow in case of cycloheptanone (97:3 diastereoselectivity. Enantiomeric excess for the syn isomer was found to be 87% in water and 97% in absolute EtOH. As an illustration, enantioenriched nitroketone 5e was subjected to hydrogenation followed by acetylation to give the octahydroindole scaffold 10 (two steps, 45%, trans/cis ∼ 3:1) (Scheme 4), which are found in several bioactive natural products, known as glycosidase inhibitors and glycomimetics, to name a few.25

Table 5. Asymmetric Michael Addition with Different Ketones and Aldehydes Using Catalyst 2a,b

Scheme 4. Synthesis of Octahydroindole Derivative 10

To conclude, the synthesis of different pyrrolidineoxadiazolone conjugates as new organocatalysts have been achieved, and utility of these catalysts in asymmetric Michael reactions have also been demonstrated. Some of these new catalysts afforded enantiopure Michael adducts (up to 99% ee and syn/anti > 97:3) in high chemical yields (up to 97%), most cases in short reaction time. An optically active bicyclic compound, octahydroindole, has also been synthesized as an extension of the studies. Further usefulness and broader applications of these catalysts and analogues are currently in progress in our laboratory.

a

Reaction conditions: ketones and aldehydes (5 equiv), nitrostyrene (1 equiv), catalyst 2 (10 mol %), TEA (10 mol %), absolute EtOH, RT. bIsolated yields, dr determined by the 1H NMR of the crude product, dr >97:3, syn-isomer is major; chiral HPLC was used to determine enantiomeric excess (ee), corresponds to the syn diastereomer.

molecules in water will have great deal of attention as the catalytic system will mimic the natural enzymatic reactions. In view of developing new generation of organocatalysts to be effective in water,10 we synthesized catalyst 9 (Scheme 3, see

■

EXPERIMENTAL SECTION

General Remarks. All reactions were performed under dry conditions using commercial grade reagents and dry solvents. Chromatographic purification of the products was accomplished using silica gel (100−200 mesh), and thin-layer chromatography (TLC) was performed on aluminum backed silica gel 60 with F254 indicator. The 1H, 19F, and 13C NMR spectra were recorded on 400, 376, and 100 MHz, respectively. Chemical shifts (δ) of 1H NMR and 13 C NMR are expressed in parts per million (ppm). GC−MS experiments were performed on Agilent 6890 series GC coupled mass selective detector, with HP-5MS capillary column. Purity was determined by Shimadzu Prominence LC-20AD Binary pump, Shimadzu SIL-HTC autosampler and Applied Biosystem API-2000 triple quadruple mass spectrometer equipped with ESI source. Chiral high performance liquid chromatography (HPLC) was performed using IA, IC, IG, AD-H, and OD-H columns using either ethanol or a mixture of solvents viz., hexane, ethyl acetate and adding diethyl amine, where appropriate, as eluent. Elemental analyses (C, H, and N) were recorded using PerkinElmer 2400 elemental analyzer. HRMS spectra were recorded using Xevo G2-S QToF instrument. (S)-1-Pyrrolidin-2-yl-methanol (IIa). Compound IIa was prepared from Ia (3.0 g, 26.05 mmol) following the literature procedure23 in 94% crude yield (2.49 g) as a light yellow liquid. Crude was forwarded to next step. 1H NMR (400 MHz, CDCl3) δ 3.59−3.49 (m, 1H), 3.32−3.24 (m, 2H), 2.92−2.82 (m, 4H), 1.93−1.61 (m, 3H), 1.41− 1.35 (m, 1H). Anal. Calcd for C5H11NO: C, 59.37; H, 10.96; N, 13.85. Found: C, 59.30; H, 11.02; N, 13.78. (S)-2-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (IIIa). Compound IIIa was prepared from IIa (2.0 g, 19.74 mmol) following the literature procedure16,23 in 58% yield (2.3 g) as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 4.75−4.73 (br s, 1H), 3.94 (br s, 1H), 3.62−3.56 (m, 2H), 3.42 (br s, 1H), 3.32−3.30 (m,

Scheme 3. Michael Addition of Cyclohexanone to Phenyl Nitrostyrene with Catalyst 9

also Supporting Information) containing a bulky substituent at 3-position of the pyrrolidine ring, starting from commercially available (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester. On the basis of the previous findings,11d we hypothesized that due to high hydrophobicity, analogue 9 will be partially soluble in water and will form a pseudo organic phase with hydrophobic nitrostyrene and ketone in water medium, and as a result the Michael reaction will proceed efficiently. Accordingly, we investigated the Michael addition between nitrostyrene 3a and ketone 4 both in water and ethanol as solvents for a head-to-head comparison (Scheme 3). Gratifyingly, this hydrophobic catalyst 9 indeed afforded the desired 1056

DOI: 10.1021/acs.joc.8b02393 J. Org. Chem. 2019, 84, 1053−1063

Note

The Journal of Organic Chemistry 1H), 2.02−1.95 (m, 1H), 1.81−1.75 (m, 2H), 1.45 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.9, 80.1, 67.3, 59.9, 47.4, 28.5, 28.3, 23.9; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C10H19NO3Na 224.1263, found 224.1257. (S)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (IVa). Compound IVa was prepared from IIIa (1.0 g, 4.96 mmol) following the literature procedure16,23 in 62% yield (1.1 g) as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.84 Hz, 2H), 7.32 (br s, 2H), 4.07−3.87 (m, 3H), 3.26 (br s, 2H), 2.43 (s, 3H), 1.95−1.78 (m, 4H), 1.39−1.35 (2s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.3 and 153.9 (rotamers), 144.8, 132.7, 129.7, 127.7, 79.9, and 79.4 (rotamers), 69.8, 55.4, 46.7, and 46.3 (rotamers), 28.2, 27.4, 23.6, and 22.7 (rotamers), 21.5; HRMS (ESITOF) m/z [M + Na]+ calcd for C17H25NO5SNa 378.1351, found 378.1367. (S)-2-Cyanomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (Va). To a stirred solution of (S)-2-(toluene-4-sulfonyloxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester IVa (6.0 g, 16.89 mmol) in dry DMSO (60 mL) was added sodium cyanide (2.48 g, 50.68 mmol) portion wise at room temperature. Then the reaction mixture was stirred at 90 °C for 8 h. After completion of the reaction, it was quenched with ice water and the organic components were extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give crude product which was purified by silica gel chromatography using ethyl acetate−hexane as eluent to yield the desired product (S)-2-cyanomethyl-pyrrolidine-1-carboxylic acid tertbutyl ester Va in 68% yield (2.42 g) as a colorless liquid. [α]D25 = −91.17 (c 0.51, CHCl3); IR (Neat) υ̃ 2248 (−CN), 1693 (−NCOOtBu) cm−1; 1H NMR (400 MHz, CDCl3) δ 3.99 (br s, 1H), 3.38 (br s, 2H), 2.80−2.55 (m,1H), 2.14−1.84 (m, 4H), 1.43 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.3 and 153.7 (rotamers), 117.8 and 117.5 (rotamers), 80.2 and 79.7 (rotamers), 53.5, 46.9, and 46.5 (rotamers), 31.1 and 30.2 (rotamers), 28.2, 23.4, and 22.9 (rotamers), 22.6 and 22.0 (rotamers); GC−MS: 210 (M)+; Chiral HPLC using Chiralpak 1A, EtOH, flow rate 0.5 mL/min, tR (S) = 7.70 min. Anal. Calcd for C11H18N2O2: C, 62.83; H, 8.63; N, 13.32. Found: C, 62.78; H, 8.67; N, 13.28. (S)-2-(N-Hydroxycarbamimidoylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (VIa). To a stirred solution of (S)-2cyanomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester Va (2.4 g, 11.42 mmol) in ethanol (20 mL) was added 50% aqueous hydroxylamine (3.7 mL, 57.1 mmol) and stirred at room temperature for 48 h. After completion of the reaction solvent was evaporated, water (20 mL) was added and extracted with ethyl acetate (3 × 100 mL). The combined organic part was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. After evaporation of solvent the crude compound of (S)-2-(N-hydroxycarbamimidoylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester VIa was obtained in 83% yield (2.3 g) as a white solid, which was forwarded to next step without further purification. mp = 155−157 °C; [α]D25 = −51.90 (c 0.13, CHCl3); 1H NMR (400 MHz, DMSOd6) δ 8.85 (br s, 1H), 5.26 (br s, 2H), 3.93 (br s, 1H), 3.22−3.20 (m, 2H), 2.41−2.38 (m, 1H), 1.88−1.70 (m, 5H), 1.40 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.6, 152.3, and 151.4 (rotamers), 79.4, 55.2, 46.4, 35.7, 29.5, 28.3, 23.2, and 22.6 (rotamers); Chiral HPLC using Chiralpak 1A, EtOH, flow rate 0.5 mL/min, tR (S) = 7.09 min; LC−MS (ESI) 244.0 [M + H]+; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C11H21N3O3Na 266.1481, found 266.1482. (S)-2-(5-Oxo-4,5-dihydro-[1,2,4]oxadiazol-3-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (VIIa). To a stirred solution of (S)-2-(N-hydroxycarbamimidoylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester VIa (2.3 g, 9.45 mmol) in dry THF (25 mL) was added carbonyl diimidazole (2.3 g, 14.18 mmol) and refluxed at 70 °C for 16 h. Then, the reaction mixture was cooled to room temperature and solvent was evaporated. The crude material was dissolved in ethyl acetate, extracted with 1 (M) NaOH solution (50 mL × 2). The sodium hydroxide layer was acidified (pH = 2−4) with 4 (N) HCl solution, then extracted with dichloromethane (100 mL × 2), washed with saturated sodium chloride solution, dried over sodium sulfate

and concentrated to give light yellow solid. The solid was washed with 30% diethyl ether in pentane to obtain (S)-2-(5-oxo-4,5-dihydro[1,2,4]oxadiazol-3-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester VIIa in 63% yield (1.6 g) as a white solid. [α]D25 = +13.6 (c 0.6, CHCl3); IR (Neat) υ̃ 1778 (−NCO−), 1644 (−NCOtBu) cm−1; 1 H NMR (400 MHz,CDCl3) δ 3.99 (br s, 1H), 3.37 (br s, 2H), 2.86− 2.83 (m, 1H), 2.69−2.67 (m, 1H), 2.09−2.04 (m, 1H), 1.90−1.82 (m, 3H), 1.45 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.1, 157.4, 155.4, 80.8, 54.4, 46.8, 31.2, 28.3, 23.4; Chiral HPLC using Chiralpak IA, EtOH, flow rate 0.5 mL/min, tR (S) = 7.76 min; LC− MS (ESI) 270.1 [M + H]+. Anal. Calcd for C12H19N3O4: C, 53.52; H, 7.11; N, 15.60. Found: C, 53.47; H, 7.17; N, 15.54. 3-(S)-1-Pyrrolidin-2-ylmethyl-2H-[1,2,4]oxadiazol-5-one hydrochloride (2). 4.0 M HCl in 1,4-dioxane (10 mL) was added to (S)2-(5-oxo-4,5dihydro-[1,2,4]oxadiazol-3-ylmethyl)-pyrrolidine-1carboxylic acid tert-butyl ester VIIa (500 mg, 1.85 mmol) at ice cold condition and stirred at room temperature for 4 h. After completion of the reaction, concentrated in vacuo. Then the crude product was washed with diethyl ether and dried to give 3-(S)-1-pyrrolidin-2ylmethyl-2H-[1,2,4]oxadiazol-5-one hydrochloride 2 in 97% yield (370 mg) as a white solid. [α]D25 = +29.3 (c 0.5, MeOH); IR (Neat) υ̃ 1771 (−NCO−) cm−1; 1H NMR (400 MHz, DMSO-d6) δ 12.57 (br s, 1H), 9.45−9.27 (br s, 2H), 3.79 (br s, 1H), 3.19−3.16 (br s, 2H), 2.99 (t, J = 8.04 Hz, 2H), 2.14−2.12 (m, 1H), 1.95−1.82 (m, 2H), 1.70−1.63 (m, 1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 159.3, 156.8, 54.9, 44.3, 29.5, 27.0, 22.7; Chiral HPLC using Chiralpak IA, EtOH, flow rate 0.5 mL/min, tR (S) = 7.76 min; LC− MS (ESI) 170.0 [M − Cl]+; HRMS (ESI-TOF) m/z [M − Cl]+ calcd for C7H12N3O2 170.0930, found 170.0926. (R)-1-Pyrrolidin-2-yl-methanol (IIb). Compound IIb was prepared from Ib (3.0 g, 26.05 mmol) following the literature procedure23 in 91% crude yield (2.41g) as a light yellow liquid. Crude was forwarded to next step. 1H NMR (400 MHz, CDCl3) δ 3.54−3.49 (m, 1H), 3.32−3.24 (m, 2H), 2.94−2.77 (m, 2H), 2.71 (br s, 2H), 1.84−1.64 (m, 3H), 1.43−1.36 (m, 1H). Anal. Calcd for C5H11NO: C, 59.37; H, 10.96; N, 13.85. Found: C, 59.32; H, 11.05; N, 13.77. (R)-2-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (IIIb). Compound IIIb was prepared from IIb (2.3 g, 22.73 mmol) following the literature procedure16,23 in 59% yield (2.72 g) as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 4.75−4.73 (br s, 1H), 3.95 (br s, 1H), 3.62−3.56 (m, 2H), 3.44−3.43 (br s, 1H), 3.32−3.28 (m, 1H), 2.02−1.95 (m, 1H), 1.82−1.76 (m, 2H), 1.46 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.7, 79.9, 66.9, 59.9, 47.3, 28.4, 28.3, 23.8; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C10H19NO3Na 224.1263, found 224.1257. (R)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (IVb). Compound IVb was prepared from IIIb (2.5 g, 12.42 mmol) following the literature procedure16,23 in 63% yield (2.8 g) as a colorless liquid.1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.12 Hz, 2H), 7.34−7.32 (br s, 2H), 4.08−3.87 (m, 3H), 3.28−3.26 (m, 2H), 2.43 (s, 3H), 1.94−1.79 (m, 4H), 1.39−1.35 (2s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.3 and 153.9 (rotamers), 144.8 and 144.6 (rotamers), 132.7, 129.8, 127.7, 79.8, and 79.4 (rotamers), 69.8, 55.4, 46.8, and 46.3 (rotamers), 28.2, 27.5, 23.7, and 22.7 (rotamers), 21.5; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H25NO5SNa 378.1351, found 378.1367. (R)-2-Cyanomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (Vb). Compound Vb was prepared from IVb (4.0 g, 11.25 mmol) employing same protocol that was used for compound Va in 63% yield (1.51 g) as a colorless liquid. [α]D25 = +95.0 (c 0.4, CHCl3); IR (Neat) υ̃ 2248 (−CN), 1693 (−NCOOtBu) cm−1; 1H NMR (400 MHz, CDCl3) δ 3.98 (br s, 1H), 3.43−3.39 (m, 2H), 2.86−2.54 (m, 2H), 2.17−1.85 (m, 4H), 1.45 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.5 and 153.8 (rotamers), 118.0 and 117.7 (rotamers), 80.3 and 79.9 (rotamers), 53.6, 47.1, and 46.6 (rotamers), 31.2 and 30.4 (rotamers), 28.4, 23.6, and 23.1 (rotamers), 22.8 and 22.3 (rotamers); GC−MS: 210.1 (M)+; Chiral HPLC using Chiralpak IA, EtOH, flow rate 0.5 mL/min, tR (R) = 7.26 min. Anal. Calcd for C11H18N2O2: C, 62.83; H, 8.63; N, 13.32. Found: C, 62.77; H, 8.66; N, 13.26. 1057

DOI: 10.1021/acs.joc.8b02393 J. Org. Chem. 2019, 84, 1053−1063

Note

The Journal of Organic Chemistry (R)-2-(N-Hydroxycarbamimidoylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (VIb). Compound VIb was prepared from Vb (1.5 g, 7.13 mmol) employing same protocol that was used for compound VIa in 75% yield (1.3 g) as a white solid. mp = 158−160 °C; [α]D25 = +37.0 (c 0.28, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ 8.85 (br s, 1H), 5.26 (br s, 2H), 3.93 (br s, 1H), 3.22−3.20 (m, 2H), 2.42−2.39 (m, 1H), 1.80−1.70 (m, 5H), 1.40 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.6, 152.3, and 151.4 (rotamers), 79.4, 55.2, 46.4, 35.7, 29.5, 28.3, 23.2, and 22.6 (rotamers); Chiral HPLC using Chiralpak 1A, EtOH, flow rate 0.5 mL/min, tR (R) = 7.12 min; LC−MS (ESI) 244.0 [M + H]+; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C11H21N3O3Na 266.1481, found 266.1482. (R)-2-(5-Oxo-2,5-dihydro-[1,2,4]oxadiazol-3-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (VIIb). Compound VIIb was prepared from VIb (1.1 g, 4.52 mmol) employing same protocol that was used for compound VIIa in 57% yield (690 mg) as a white solid. [α]D25 = −12.45 (c 0.48, CHCl3); IR (Neat) υ̃ 1784 (−NCO−), 1666 (−NCOtBu) cm−1; 1H NMR (400 MHz, CDCl3) δ 3.99 (br s, 1H), 3.37 (t, J = 6.60 Hz, 2H), 2.86−2.70 (m, 2H), 2.10−2.04 (m, 1H), 1.93−1.77 (m, 3H), 1.45 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.1, 157.4, 155.4, 80.8, 54.4, 46.8, 31.3, 28.3, 23.4; Chiral HPLC using Chiralpak AD-H, EtOH, flow rate 0.5 mL/min, tR (R) = 6.31 min; LC−MS (ESI) 270.2 [M + H]+. Anal. Calcd for C12H19N3O4: C, 53.52; H, 7.11; N, 15.60. Found: C, 53.46; H, 7.16; N, 15.57. 3-(R)-1-Pyrrolidin-2-ylmethyl-2H-[1,2,4]oxadiazol-5-one hydrochloride (8). Compound 8 was prepared from VIIb (200 mg, 0.74 mmol) employing same protocol that was used for compound 2 in 98% yield (149 mg) as a white solid. [α]D25 = −31.48 (c 0.5, MeOH); IR (Neat) υ̃ 1776 (−NCO−) cm−1; 1H NMR (400 MHz, DMSO-d6) δ 12.57 (br s, 1H), 9.43−9.32 (br s, 2H), 3.80 (br s, 1H), 3.20−3.17 (m, 2H), 3.03−2.98 (m, 2H), 2.17−2.09 (m, 1H), 1.97−1.84 (m, 2H), 1.70−1.63 (m, 1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 159.3, 156.9, 54.9, 44.3, 29.5, 27.0, 22.8; Chiral HPLC using Chiralpak 1A, (EtOH/DEA:100:0.1), flow rate 0.5 mL/min, tR (R) = 5.17 min; LC−MS (ESI) 170.0[M + H]+; HRMS (ESI-TOF) m/z [M − Cl]+ calcd for C7H12N3O2 170.0930, found 170.0926. Synthesis of (S)-3-Pyrrolidin-2-yl-4H-[1,2,4]oxadiazol-5-one hydrochloride (1, Supporting Information). The catalyst 1 was synthesized from commercially available (S)-2-cyano-pyrrolidine-1carboxylic acid tert-butyl ester VIII. According to literature procedure VIII was converted to X.22 Deprotection of BOC-compound X was performed by 4.0 M HCl in 1,4-dioxane and the crude compound was titurated with diethyl ether and dried. Compounds IX, X and 1 were prepared following the literature procedure.22 (S)-3-Pyrrolidin-2-yl-4H-[1,2,4]oxadiazol-5-one hydrochloride (1).22 4.0 M HCl in 1,4-dioxane (10 mL) was added to (S)-2-(5oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester X (500 mg, 1.96 mmol) at ice cold condition and stirred at room temperature for 4 h. After completion of the reaction, concentrated in vacuo. Then the crude product was washed with diethyl ether and dried to give (S)-3-pyrrolidin-2-yl-4H-[1,2,4]oxadiazol-5-one 1 in 98% yield (368 mg) as a white solid. [α]D25 = −43.76 (c 1, MeOH), [lit. [α]D25 = −43.3 (c 1.055, MeOH)]; IR (Neat) υ̃ 1787 (−NCO−) cm−1; 1H NMR (400 MHz, DMSO-d6) δ 4.66 (t, J = 7.7 Hz, 1H), 3.31−3.24 (m, 2H), 2.35−2.26 (m, 1H), 2.18−1.91 (m, 3H); 13C{1H} NMR (100 MHz, MeOD) δ 160.3, 156.1, 53.6, 46.3, 28.4, 23.3; Chiral HPLC using Chiralpak IC, (Hexane:IPA:TFA: 85:15:0.1), flow rate 1.0 mL/min, tR (S) = 4.18 min; LC−MS (ESI) 156.0 [M + H]+. Synthesis of 3-[(2R,4S)-4-(4-tert-Butyl-phenoxy)-pyrrolidin2ylmethyl]-4H-[1,2,4]oxadiazol-5-one Hydrochloride (9, Supporting Information). Starting from XI, XIII was synthesized (via prolinate intermediate XII) by Mitsunobu reaction. After deprotection of N-CBZ in XIII, XVI was obtained by reduction of ester via the corresponding N-BOC protected intermediate XV. O-Tosylation followed by cyanation provided XVIII. The cyano derivative was converted to cis-derivative XX.22 After deprotection of cis-derivative XX catalyst 9 was obtained. Synthesis of (2S,4S)-4-(4-tert-Butyl-phenoxy)-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (XIII). To a stirred solution of (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-

benzyl ester 2-methyl ester XII (5.0 g, 17.90 mmol) in THF (60 mL) were added 4-tert-butyl phenol (4.03 g, 26.85 mmol), triphenyl phosphine (7.04 g, 26.85 mmol) and DEAD (40% in THF) (13.42 mL, 26.85 mmol) sequentially at 0 °C. Then the resulting reaction mixture was stirred at room temperature for 16 h. Reaction was monitored by TLC and LC−MS, after completion of the reaction, solvent was removed and 20% diethyl ether in pentane was added, then precipitation was filtered, filtrate was concentrated and purified by column chromatography to get (2S,4S)-4-(4-tert-butyl-phenoxy)pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester XIII in 54% yield (4.0 g) as a light yellow liquid. [α]D25 = −45.81 (c 0. 6, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.35−7.25 (m, 7H), 6.70 (d, J = 8.2 Hz, 2H), 5.21−5.06 (m, 2H), 4.87 (br s, 1H), 4.61−4.51 (m, 1H), 3.80−3.73 (m, 4H), 3.63 (s, 1H), 2.53−2.40 (m, 2H), 1.27 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.1 and 171.8 (rotamers), 154.7 and 154.3 (rotamers), 144.2, 136.5, and 136.5 (rotamers), 128.4, 128.3, 128.0, 127.9, 127.8, 127.7, 126.3, 115.1, 75.3, 74.4, 67.2 and 67.1 (rotamers), 58.0 and 57.8 (rotamers), 52.1 and 51.8 (rotamers), 36.6, 35.6, 34.0, 31.4; Chiral HPLC using Chiralpak IA, (Hexane/EtOH/IPA: 80:20:0.1), flow rate 1.0 mL/min, tR = 6.99 min; LC−MS (ESI) 412.2 [M + H]+. Anal. Calcd for C24H29NO5: C, 70.05; H, 7.10; N, 3.40. Found: C, 70.01; H, 7.16; N, 3.37. (2S,4S)-4-(4-tert-Butyl-phenoxy)-pyrrolidine-2-carboxylic acid methyl ester (XIV). To a stirred solution of (2S,4S)-4-(4-tert-butylphenoxy)-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester XIII (1.0 g, 2.43 mmol) in ethyl acetate was added Pd/C (100 mg/g) and stirred at room temperature for 16 h under hydrogen atmosphere. After completion of the reaction filtered through Celite bed, washed with ethyl acetate. Filtrate was concentrated to give (2S,4S)-4-(4-tert-butyl-phenoxy)-pyrrolidine-2-carboxylic acid methyl ester XIV in 100% yield (670 mg) as colorless liquid. [α]D25 = −22.0 (c 0.6, CHCl3); IR (Neat) υ̃ 1739 (−NCO−) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.7 Hz, 2H), 4.78−4.76 (m, 1H), 3.84−3.81 (m, 1H), 3.70 (s, 3H), 3.33 (d, J = 12.48 Hz, 1H), 3.05−3.01(m, 1H), 2.43−2.25 (m, 2H), 1.27(s, 9H); 13 C{1H}NMR (100 MHz, CDCl3) δ 174.5, 154.6, 143.6, 126.2, 115.0, 59.1, 52.7, 52.1, 36.7, 33.9, 31.4; Chiral HPLC using Chiralpak IA, (Hexane/EtOH/IPA: 80:20:0.1), flow rate 1.0 mL/min, tR = 5.76 min; LC−MS (ESI) 278.8 [M + H]+; HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H24NO3 278.1757, found 278.1774. (2S,4S)-4-(4-tert-Butyl-phenoxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (XV). To a stirred solution of (2S,4S)-4-(4-tert-butyl-phenoxy)-pyrrolidine-2-carboxylic acid methyl ester XIV (650 mg, 2.34 mmol) in THF (25 mL) was added di-tertbutyl dicarbonate (0.8 mL, 3.51 mmol) at 0 °C, after that NaHCO3 (393 mg, 4.69 mmol) in water (25 mL) was added at same temperature. Then the resulting mixture was stirred at room temperature for 16 h. After completion of the reaction, diluted with water and extracted with ethyl acetate, the organic part was washed with saturated sodium chloride solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel (100−200 mesh) column chromatography using 30% ethyl acetate in hexane as an eluent. After evaporation of solvent (2S,4S)-4-(4-tert-butyl-phenoxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester XV was obtained in 98% yield (900 mg) as a colorless liquid. [α]D25 = −24.0 (c 0. 5, CHCl3); IR (Neat) υ̃ 1754 (−NCO−) cm−1, 1702 (−CCO) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.28−7.25 (m, 2H), 6.72−6.99 (m, 2H), 4.84 (br s, 1H), 4.51−4.39 (m, 1H), 3.75−3.66 (m, 4H), 2.47−2.41 (m, 2H), 1.46 and 1.41 (2 s, 9H, rotamers), 1.28 and 1.27 (2 s, 9H, rotamers); 13C{1H} NMR (100 MHz, CDCl3) δ 172.6 and 172.2 (rotamers), 154.3 and 154.2 (rotamers), 153.7, 144.0, 126.3, 115.0, and 114.9 (rotamers), 80.3, 80.2, and 80.1 (rotamers), 75.3, 74.3, 57.9, and 57.5 (rotamers), 52.2, 52.0, and 51.9 (rotamers), 51.5, 36.4, 35.5, 34.0, 31.4, 28.3, and 28.2 (rotamers); Chiral HPLC using Chiralpak IA EtOH, flow rate 0.5 mL/min, tR = 7.33 min; LC−MS (ESI) 378.2 [M + H]+. Anal. Calcd for C21H31NO5: C, 66.82; H, 8.28; N, 3.71. Found: C, 66.76; H, 8.33; N, 3.68. 1058

DOI: 10.1021/acs.joc.8b02393 J. Org. Chem. 2019, 84, 1053−1063

Note

The Journal of Organic Chemistry (2S,4S)-4-(4-tert-Butyl-phenoxy)-2-hydroxymethyl-pyrrolidine-1carboxylic acid tert-butyl ester (XVI). To a stirred solution of (2S,4S)-4-(4-tert-butyl-phenoxy)-pyrrolidine-1,2-dicarboxylic acid 1tert-butyl ester 2-methyl ester XV (800 mg, 2.21 mmol) in THF (10 mL) was added LiBH4 (95 mg, 4.37 mmol) at 0 °C and stirred at room temperature for 48 h. After completion of the reaction, quenched with ice water at 0 °C and extracted with ethyl acetate, the organic part was washed with saturated sodium chloride solution, dried over anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel (100−200 mesh) chromatography using ethyl acetate in hexane as an eluent to get (2S,4S)-4-(4-tert-butyl-phenoxy)-2hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester XVI in 93% yield (720 mg) as colorless sticky liquid. [α]D25 = −35.0 (c 0. 5, CHCl3); IR (Neat) υ̃ 1676 (−NCO−) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.64 Hz, 2H), 6.77 (d, J = 8.68 Hz, 2H), 4.80 (br s, 1H), 4.41 (br s, 1H), 4.15 (br s, 1H), 3.92−3.88 (m, 1H), 3.66−3.58 (m, 4H), 2.38−2.31 (m, 1H), 1.94 (d, J = 12.8 Hz, 1H), 1.46 (s. 9H), 1.28 and 1.24 (2S, 9H, rotamers); 13C{1H}NMR (100 MHz, CDCl3) δ 156.8, 154.4, 144.0, 126.4, 115.3, and 114.8 (rotamers), 80.6, 76.7, 75.0, 67.9, 59.6, 53.4, and 52.9 (rotamers), 34.3 and 34.0 (rotamers), 31.4, 28.4; Chiral HPLC using Chiralpak IA Hexane/EtOH/IPA: 80/20/0.1), flow rate 1.0 mL/min, tR = 5.46 min; LC−MS (ESI) 350.0 [M + H]+. Anal. Calcd for C20H31NO4: C, 68.74; H, 8.94; N, 4.01. Found: C, 68.69; H, 8.99; N, 3.95. (2S,4S)-4-(4-tert-Butyl-phenoxy)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (XVII). Compound XVII was prepared from XVI (1.2 g, 3.43 mmol) employing same protocol that was used for compound IVa in 95% yield (1.65 g) as a colorless liquid. [α]D25 = −32.0 (c 0.47, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.0 Hz, 2H), 7.32−7.25 (m, 4H), 6.63 (br s, 2H), 4.78 (br s, 1H), 4.30−4.03 (m, 3H), 3.63 (br s, 1H), 3.48 (d, J = 12.36 Hz, 1H), 2.41 (s, 3H), 2.27−2.17 (m, 2H), 1.41 (s, 9H), 1.29 (s, 9H); 13C{1H}NMR (100 MHz, CDCl3) δ 154.3 and 153.9 (rotamers), 144.7 and 144.0 (rotamers), 132.8, 130.0, and 129.8 (rotamers), 127.9, 126.3, and 125.9 (rotamers), 115.1, 80.4, and 80.1 (rotamers), 75.9 and 75.1 (rotamers), 70.0 and 69.4 (rotamers), 55.2, 52.5, and 52.1 (rotamers), 34.0 and 33.9 (rotamers), 33.1, 31.4, 28.3, 21.6; Chiral HPLC using Chiralpak IG (Hexane/EA/EtOH/IPA: 70/ 15/15/0.1), flow rate 1.0 mL/min, tR = 4.77 min; LC−MS (ESI) 504.2 [M + H]+. Anal. Calcd for C27H37NO6S: C, 64.39; H, 7.41; N, 2.78. Found C, 64.33; H, 7.47; N, 2.72. (2R,4S)-4-(4-tert-Butyl-phenoxy)-2-cyanomethyl-pyrrolidine-1carboxylic acid tert-butyl ester (XVIII). Compound XVIII was prepared from XVII (1.6 g, 3.18 mmol) employing same protocol that was used for compound Va in 45% yield (510 mg) as a colorless liquid. [α]D25 = −63.82 (c 0.35, CHCl3); IR (Neat) υ̃ 2249 (−CN) cm−1, 1697 (−NCO−) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.30 (br s, 2H), 6.77 (d, J = 7.52 Hz, 2H), 4.88 (br s, 1H), 4.21 (br s, 1H), 3.68−3.63 (br s, 2H), 3.05−2.77 (m, 2H), 2.34 (br s, 2H), 1.48 and 1.44 (2 s, 9H, rotamers), 1.29 (s, 9H); 13C{1H}NMR (100 MHz, CDCl3) δ 154.3 and 154.2 (rotamers), 153.9 and 153.5 (rotamers), 144.2, 126.4, and 126.3 (rotamers), 117.9, 115.2, 114.7, and 114.6 (rotamers), 80.8 and 80.4 (rotamers), 75.8 and 75.1 (rotamers), 53.7, 52.5, and 52.3 (rotamers), 36.2 and 35.2 (rotamers), 34.0, 31.3, 28.3, 23.2, and 22.4 (rotamers); Chiral HPLC using Chiralpak IA, (Hexane/EtOH/IPA: 80:20:0.1), flow rate 1.0 mL/min, tR = 4.30 min; LC−MS (ESI) 359.2 [M + H]+; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C21H30N2O3Na 381.2154, found 381.2173. (2R,4S)-4-(4-tert-Butyl-phenoxy)-2-(N-hydroxycarbamimidoylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (XIX). Compound XIX was prepared from XVII (500 mg, 1.39 mmol) employing same protocol that was used for compound VIa in 74% yield (400 mg) as a white solid. [α]D25 = −52.0 (c 0. 5, CHCl3); IR (Neat) υ̃ 1678 (−NCO−) cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 7.29 (d, J = 8.64 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 5.22 (s, 2H), 4.9 (br s, 1H), 4.10−4.07 (m, 1H), 3.67−3.63 (m, 1H), 3.36 (br s, 1H), 2.66−2.60 (m, 1H), 2.28−2.25 (m, 1H), 2.20−1.98 (m, 1H), 1.40 (s, 9H), 1.25 (s, 9H); 13C{1H}NMR (100 MHz, CDCl3) δ 154.6 and 154.2 (rotamers), 152.1 and 151.3 (rotamers), 143.6, 126.2, and

126.1 (rotamers), 115.0 and 114.7 (rotamers), 79.8, 76.0, and 75.4 (rotamers), 55.2, 52.1, 36.6, 35.6, 33.9, 31.3, 28.3; Chiral HPLC using Chiralpak IA, EtOH, flow rate 0.5 mL/min, tR = 8.21 min; LC−MS (ESI) 392.1 [M + H]+; HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H34N3O4 392.2550, found 392.2573. (2R,4S)-4-(4-tert-Butyl-phenoxy)-2-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-ylmethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (XX). Compound XX was prepared from XIX (375 mg, 0.95 mmol) employing same protocol that was used for compound VIa in 37% yield (150 mg) as a colorless semisolid. [α]D25 = +6.4 (c 0.45, CHCl3); IR (Neat) υ̃ 1785 (−NCO−) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.8 Hz, 2H), 4.93 (br s, 1H), 4.12 (br s, 1H), 3.72−3.69 (m, 2H), 3.03−3.02 (m, 2H), 2.31−2.20 (m. 2H), 1.46 (s, 9H), 1.29 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.1, 157.8, 155.2, 154.2, 144.3, 126.5, 114.6, 81.4, 75.8, 54.1, 52.7, 36.9, 34.1, 32.5, 31.4, 28.3; Chiral HPLC using Chiralpak IA, (Hexane/IPA/TFA: 85:15:0.1), flow rate 1 mL/min, tR = 6.41 min; LC−MS (ESI) 418.2 [M + H]+. Anal. Calcd for C22H31N3O5: C, 63.29; H, 7.48; N, 10.06. Found: C, 63.23; H, 7.56; N, 10.01. 3-[(2R,4S)-4-(4-tert-Butyl-phenoxy)-pyrrolidin-2-ylmethyl]-4H[1,2,4]oxadiazol-5-one hydrochloride (9). Compound 9 was prepared from XIX (150 mg, 0.36 mmol) employing same protocol that was used for compound VIIa in 98% yield (125 mg) as a gray solid. [α]D25 = +46.48 (c 0.4, CHCl3); IR (Neat) υ̃ 1777 (−NCO−) cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.32 (d, J = 8.72 Hz, 2H), 6.88 (d, J = 8.72 Hz, 2H), 5.09 (br s, 1H), 4.03−3.99 (m, 1H), 3.56− 3.49 (m, 2H), 3.32 (s, 1H), 3.09 (d, J = 7.32 Hz, 2H), 2.69−2.62 (m, 1H), 1.96−1.91 (m, 1H), 1.25 (s, 9H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 159.4, 156.7, 154.0, 143.5, 126.2, 115.0, 74.8, 54.1, 49.8, 35.9, 33.7, 31.2, 27.8; Chiral HPLC using Chiralpak IG, (Hexane/ EtOH/IPA: 80:20:0.1), flow rate 1 mL/min, tR = 6.60 min; LC−MS (ESI) 318.3 [M + H]+; HRMS (ESI-TOF) m/z [M − Cl]+ calcd for C17H24N3O3 318.1818, found 318.1837. General Procedure: Michael Addition Reaction of Carbonyls and Nitroolefins. To a stirred solution of catalyst (10 mol %) in absolute ethanol or water (1.0 mL), carbonyls (5.0 mmol) and TEA (10 mol %) were added at room temperature, and the resulting mixture was stirred for 10 min. Then nitroolefins (1.0 mmol) were added, and the reaction mixture was stirred further for 1.5−24 h at room temperature. The completion of the reaction was monitored by GC−MS and then quenched with saturated solution of NH4Cl (10 mL) and extracted with dichloromethane (10−15 mL). The combined organic layers were dried over Na2SO4, and the solvent was removed in vacuum. In most of the cases, the products were isolated in sufficiently pure form without performing any chromatography. In some cases, the crude products were purified by silica gel chromatography (Hexane/EtOAc as eluent) and characterized. The reported literature values of 1H NMR and specific rotation were used to establish relative and absolute configurations of the products through comparison. Chiral HPLC was employed to determine enantiomeric excess. (S)-2-((R)-2-Nitro-1-phenyl-ethyl)-cyclohexanone (5a).20b White solid (204 mg, 82% yield); [α]D25 = −28.89 (c 1.0, CHCl3), [lit. [α]D20 = −27.0 (c 1.0, CHCl3)]; 1H NMR (400 MHz, CDCl3) δ 7.31−7.14 (m, 5H), 4.92 (dd, J = 4.4 and 12.56 Hz, 1H), 4.62 (dd, J = 10.08 and 12.2 Hz, 1H), 3.77−3.72 (m, 1H), 2.71−2.64 (m, 1H), 2.48−2.34 (m, 2H), 2.06 (br s, 1H),1.74−1.60 (m, 4H), 1.26−1.18 (m, 1H); HPLC analysis: 98% ee, Chiral HPLC using Chiralpak 1A, EtOH, flow rate 0.5 mL/min, tR = 9.14 min (minor) and 10.30 min (major). (R)-2-((S)-2-Nitro-1-phenyl-ethyl)-cyclohexanone (5a′).20c White solid (210 mg, 85% yield); [α]D25 = +29.97 (c 0.95, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.32−7.14 (m, 5H), 4.92 (dd, J = 4.4and 12.4 Hz, 1H), 4.61 (dd, J = 9.88 and 12.4 Hz, 1H), 3.78−3.72 (m, 1H), 2.70−2.64 (m, 1H), 2.48−2.37 (m, 2H), 2.08−2.04 (m, 1H), 1.79−1.66 (m, 4H), 1.24−1.20 (m, 1H); HPLC analysis: 98% ee, Chiral HPLC using Chiralpak 1A, EtOH, flow rate 0.5 mL/min, tR = 8.92 min (major) and 10.02 min (minor). 1059

DOI: 10.1021/acs.joc.8b02393 J. Org. Chem. 2019, 84, 1053−1063

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The Journal of Organic Chemistry

Chiralpak 1A, (Hexane/EtOH/IPA:80/20/0.1) flow rate 1 mL/min, tR = 8.16 min (minor) and 9.38 min (major). (S)-2-((R)-2-Nitro-1-thiophen-3-yl-ethyl)-cyclohexanone (5i).20f White solid (182 mg, 72% yield); [α]D25 = −28.2 (c 0.42, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.29 (dd, J = 2.96 and 4.8 Hz, 1H), 6.98 (s, 1H), 6.92 (d, J = 3.8 Hz, 1H), 4.83 (dd, J = 4.84 and 12.4 Hz, 1H), 4.62 (dd, J = 9.4 and 12.24 Hz, 1H), 4.02−3.92 (m, 1H), 2.66 (br s, 1H), 2.47−2.32 (m, 2H), 2.08−2.06 (m, 1H), 1.82−1.55 (m, 4H), 1.30−1.21 (m, 1H); HPLC analysis: 90% ee, Chiral HPLC using Chiralpak 1A, EtOH, flow rate 0.5 mL/min, tR = 10.94 min (minor) and 12.24 min (major). (S)-2-((R)-1-Furan-3-yl-2-nitro-ethyl)-cyclohexanone (5j).20e White solid (196 mg, 83% yield); [α]D25 = −21.49 (c 0.43, CHCl3), [lit. [α]D20 = −15.6 (c 1.0, CHCl3)]; 1H NMR (400 MHz, CDCl3) δ 7.36 (s, 1H), 7.28 (s, 1H), 7.24 (s, 1H), 4.75 (dd, J = 5.52 and 12.32 Hz, 1H), 4.56 (dd, J = 9.12 and 11.96 Hz, 1H), 3.81− 3.76 (m, 1H), 2.62−2.56 (m, 1H), 2.46−2.31 (m, 2H), 2.07−2.03 (m, 1H), 1.97−1.62 (m, 3H), 1.32−1.24 (m, 1H); HPLC analysis: 95% ee, Chiral HPLC using Chiralpak1A, EtOH, flow rate 0.5 mL/ min, tR = 9.70 min (minor) and 10.79 (major). (S)-2-((R)-2-Nitro-1-pyridin-3-yl-ethyl)-cyclohexanone (5k).19 Light brown solid (164 mg, 66% yield); [α]D25 = −22.0 (c 0.48, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 4 Hz, 1H), 8.46 (s, 1H), 7.53 (d, J = 7.68 Hz, 1H), 7.27 (s, 1H), 4.94 (dd, J = 4.4 and 12.8 Hz, 1H), 4.68 (dd, J = 11.8 and 12.68 Hz, 1H), 3.83−3.79 (m, 1H), 2.75−2.68 (m, 1H), 2.49−2.33 (m, 2H), 2.08 (br s 1H), 1.83− 1.62 (m, 3H), 1.30−1.27 (m, 2H); HPLC analysis: 93% ee, Chiral HPLC using Chiralpak 1A, EtOH, flow rate 0.5 mL/min, tR = 10.47 min (major) and 11.07 (minor). (S)-2-((S)-1-Cyclopropyl-2-nitro-ethyl)-cyclohexanone (5l). Colorless liquid (102 mg, 48% yield); [α]D25 = −17.81 (c 0.5, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 4.68 (dd, J = 6.2 and 11.8 Hz, 1H), 4.49 (dd, J = 5 and 20 Hz, 1H), 2.68−2.42 (m, 1H), 2.40−2.31 (m, 3H), 2.12−2.08 (m, 1H),1.95−1.92 (m, 1H), 1.72−1.67 (m, 3H), 1.54−1.50 (m, 1H), 0.79−0.75(m, 1H), 0.54 (d, J = 8.2 Hz, 2H), 0.21−0.15 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 211.7, 78.7, 52.6, 42.7, 42.6, 32.1, 28.0, 25.4, 12.1, 5.4, 3.5; GC−MS (MNO2)+=164.25; HPLC analysis: 93% ee, Chiral HPLC using Chiralpak 1A, EtOH, flow rate 0.5 mL/min, tR = 8.37 (minor) and 9.63 min (major). Anal. Calcd for C11H17NO3: C, 62.54; H, 8.11; N, 6.63. Found: C, 62.49; H, 8.15; N, 6.57. (R)-3-((R)-2-Nitro-1-phenyl-ethyl)-tetrahydro-pyran-4-one (7a).20b White solid (222 mg, 89% yield); [α]D25 = −34.0 (c 1.0, CHCl3) [lit. [α]D20 = −27.5 (c 1.0, CHCl3)]; 1H NMR (400 MHz, CDCl3) δ 7.34−7.28 (m, 3H), 7.18−7.16 (m, 2H), 4.92 (dd, J = 4.56 and 12.72 Hz, 1H), 4.63 (dd, J = 10.08 and 12.52 Hz, 1H), 4.15−4.10 (m, 1H), 3.85−3.66 (m, 3H), 3.26 (dd, J = 8.96 and 11.32 Hz, 1H), 2.90−2.85 (m, 1H), 2.66−2.56 (m, 2H); HPLC analysis: 84% ee, Chiral HPLC using Chiralpak 1A, EtOH, flow rate 1.0 mL/min, tR = 9.013 (minor) and 10.14 min (major). (S)-3-((R)-2-Nitro-1-phenyl-ethyl)-tetrahydro-thiopyran-4-one (7b).20b White solid (146 mg, 55% yield); [α]D25 = −30.05 (c 0.95, CHCl3) [lit. [α]D20 = −26.9 (c 1.0, CHCl3)]; 1H NMR (400 MHz, CDCl3) δ 7.34−7.29 (m, 3H), 7.20−7.18 (m, 2H), 4.73 (dd, J = 4.28 and 11.92 Hz, 1H), 4.65−4.59 (m, 1H), 3.97−3.95 (m, 1H), 3.04− 2.96 (m, 3H), 2.84−2.79 (m, 2H), 2.62−2.59 (m, 1H), 2.47−2.41 (m, 1H); HPLC analysis: 85% ee, Chiral HPLC using Chiralpak 1A, (Hexane/DCM/EtOH: 50/25/25), flow Rate: 1.0 mL/min, tR = 4.29 (minor) and 12.27 min (major). (3S,4R)-3-Methyl-5-nitro-4-phenyl-pentan-2-one (7c).26 Colorless oil (66 mg, 30% yield); [α]D25 = −11.04 (c 0.2, CHCl3) [lit. [α]D25 = −6.5 (c 1.0, CHCl3)]; 1H NMR (400 MHz, CDCl3) δ 7.40− 7.27 (m, 3H), 7.21−7.14 (m, 2H), 4.76−4.59 (m, 2H), 3.69−3.63 (m, 1H), 2.99−2.95 (m, 1H), 2.23 (s, 2.38 H, syn-isomer), 1.93 (s, 0.38 H, anti-isomer), 1.20 (d, J = 6.96 Hz, 0.57 H, anti -isomer), 0.87 (d, J = 7.12 Hz, 2.9 H, syn-isomer); HPLC analysis: 75% ee, Chiral HPLC using Chiralpak 1A, (Hexane/IPA/TFA: 85/15/0.1), flow rate 1.0 mL/min, tR = 6.02 (minor) and 6.19 min (major). (R)-6-Nitro-5-phenyl-hexan-3-one (7d). Colorless oil (89 mg, 40% yield); [α]D25 = −9.7 (c 0.24, CHCl3); 1H NMR (400 MHz, CDCl3)

(S)-2-[(R)-1-(4-Fluoro-phenyl)-2-nitro-ethyl]-cyclohexanone (5b).20b White solid (228 mg, 86% yield); [α]D25 = −20.91 (c 0.96, CHCl3), [lit. [α]D20 = −19.9 (c 1.0, CHCl3)]; 1H NMR (400 MHz, CDCl3) δ 7.13−6.98 (m, 4H), 4.91 (dd, J = 4.4 and 12.48 Hz, 1H), 4.58 (dd, J = 10.1 and 12.08 Hz, 1H), 3.74 (td, J = 9.68 and 4.6 Hz, 1H), 2.67−2.60 (m, 1H), 2.48−2.33 (m, 2H), 2.07−2.03 (m,1H), 1.81−1.61 (m, 4H), 1.23−1.17 (m, 1H); 19F NMR (376 MHz, CDCl3) δ −114.29 (m, 1F); HPLC analysis: 93% ee, Chiral HPLC using Chiralpak 1A, EtOH, flow rate 0.5 mL/min, tR = 9.32 min (minor) and 10.47 min (major). (S)-2-[(R)-1-(4-Methoxy-phenyl)-2-nitro-ethyl]-cyclohexanone (5c).20b White solid (144 mg, 52% yield); [α]D25 = −23.69 (c 0.36, CHCl3), [lit. [α]D20 = −25.1 (c 1.0, CHCl3)]; 1H NMR (400 MHz, CDCl3) δ 7.06 (d, J = 8.28 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 4.90 (dd, J = 4.44 and 12.4 Hz, 1H), 4.60−4.54 (m, 1H), 3.77 (s, 3H), 3.73−3.69 (m, 1H), 2.63 (br s, 1H), 2.44−2.36 (m, 2H), 2.08−2.05 (m, 1H), 1.75−1.54 (m, 4H), 1.23−1.20 (m, 1H); HPLC analysis: 93% ee, Chiral HPLC using Chiralpak 1A, EtOH, flow rate 0.5 mL/ min, tR = 10.66 min (minor) and 11.77 min (major). (S)-2-[(R)-1-(2,4-Dimethoxy-phenyl)-2-nitro-ethyl]-cyclohexanone (5d).20d White solid (246 mg, 80% yield); [α]D25 = −37.73 (c 0.24, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.96 (d, J = 8.2 Hz, 1H), 6.42−6.38 (m, 2H), 4.81−4.76 (m, 2H), 4.10−4.38 (m, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 2.95−2.89 (m, 1H), 2.47−2.32 (m, 2H), 2.03 (br s, 1H), 1.78−1.51 (m, 4H), 1.26−1.19 (m, 1H); HPLC analysis: 94% ee, Chiral HPLC using Chiralpak 1A, EtOH, flow rate 0.5 mL/min, tR = 4.47 min (major) and 4.85 min (minor). (S)-2-[(R)-2-Nitro-1-(4-trifluoromethyl-phenyl)-ethyl]-cyclohexanone (5e). White solid (250 mg, 79% yield); [α]D25 = −26. Two (c 0.34, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.56 Hz, 2H), 7.30 (d, J = 7.52 Hz, 1H), 4.95 (dd, J = 3.96 and 12.52 Hz, 1H), 4.67 (dd, J = 9.96 and 12.48 Hz, 1H), 3.74 (td, J = 9.64 and 4.6 Hz, 1H), 2.72−2.65 (m, 1H), 2.50−2.33 (m, 2H), 2.08 (br s, 1H), 1.82− 1.62 (m, 4H), 1.28−1.19 (m,1H); 13C{1H} NMR (100 MHz, CDCl3) δ 211.2, 142.0, 130.1 (q, J = 32.45 Hz), 128.6, 125.8 (q, J = 3.80 Hz), 123.9 (q, J = 270.55 Hz), 78.3, 52.3, 43.7, 42.7, 33.2, 28.4, 25.1; 19F NMR (376 MHz, CDCl3) δ −62.68 (s, 3F); GC−MS (M-NO2)+ = 268.1; HPLC analysis: 99% ee, Chiral HPLC using Chiralpak 1A, (Hexane/EtOH/IPA: 80:20:0.1), flow rate 1.0 mL/min, tR = 8.54 min (minor) and 14.82 min (major). Anal. Calcd for C15H16F3NO3: C, 57.14; H, 5.12; N, 4.44. Found: C, 57.10; H, 5.17; N, 4.39. (S)-2-[(R)-1-(3,5-Dichloro-phenyl)-2-nitro-ethyl]-cyclohexanone (5f). Colorless liquid (240 mg, 76% yield); [α]D25 = −25.4 (c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.25 (s, 1H), 6.98 (s, 2H), 4.91 (dd, J = 4.32 and 13.08 Hz, 1H), 4.58 (dd, J = 10.2 and 12.9 Hz, 1H), 3.74−3.71 (m, 1H), 2.65−2.58 (m, 1H), 2.49−2.32 (m, 2H), 2.09−2.03 (m, 1H), 1.84−1.61 (m, 4H), 1.32−1.26 (m, 1H); 13 C{1H} NMR (100 MHz, CDCl3) 210.9, 141.5, 135.4, 128.1, 126.8, 77.9, 52.1, 43.5, 42.7, 33.2, 28.3, 25.0; GC−MS (M-NO2)+ = 268.0; HPLC analysis: 96% ee, Chiral HPLC using Chiralpak 1A, EtOH, flow rate 0.5 mL/min, tR = 7.96 min (minor) and 8.54 min (major). Anal. Calcd for C14H15Cl2NO3: C, 53.18; H, 4.78; N, 4.43. Found: C, 53.11; H, 4.85; N, 4.37. (S)-2-((R)-2-Nitro-1-p-tolyl-ethyl)-cyclohexanone (5g).20e Offwhite solid (214 mg, 82% yield); [α]D25 = −21.28 (c 0.47, CHCl3), [lit. [α]D20 = −15.3 (c 1.0, CHCl3)]; 1H NMR (400 MHz, CDCl3) δ 7.11(d, J = 6.64 Hz, 2H), 7.03 (d, J = 7.32 Hz, 2H), 4.91 (dd, J = 4.04 and 8.04 Hz, 1H), 4.59 (t, J = 11.08, 1H), 3.71 (br s, 1H), 2.64 (br s,1H), 2.44−2.36 (m, 2H), 2.30 (s, 3H), 2.06 (br s, 1H), 1.75−1.50 (m, 4H), 1.23−1.18 (m, 1H); HPLC analysis: 92% ee, Chiralpak 1A, EtOH, flow rate 0.5 mL/min, tR = 9.78 min (minor) and 11.07 min (major). (S)-2-((R)-1-Naphthalen-2-yl-2-nitro-ethyl)-cyclohexanone (5h).20b White solid (179 mg, 60% yield); [α]D25 = −36.9 (c 0.5, CHCl3), [lit. [α]D20 = −36.2 (c 1.0, CHCl3)]; 1H NMR (400 MHz, CDCl3) δ 7.82−7.71 (m, 3H), 7.62 (s, 1H), 7.48−7.45 (m, 2H), 7.28 (dd, J = 1.68 and 8.44 Hz, 1H), 5.01 (dd, J = 4.4 and 12.5 Hz, 1H), 4.72 (dd, J = 9.96 and 12.5 Hz, 1H), 3.94 (td, J = 9.96 and 4.5 Hz, 1H), 2.80−2.74 (m, 1H), 2.51−2.36 (m, 2H), 2.08−2.05 (m, 1H), 1.76−1.56 (m, 4H), 1.30−1.24 (m, 1H); HPLC analysis: 97% ee, 1060

DOI: 10.1021/acs.joc.8b02393 J. Org. Chem. 2019, 84, 1053−1063

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δ 7.31−7.30 (m, 3H), 7.21−7.19 (m, 2H), 4.69 (dd, J = 6.92 and 12.24 Hz, 1H), 4.60 (dd, J = 7.64 and 12.16 Hz, 1H), 4.03−3.99 (m, 1H), 2.87 (d, J = 6.88 Hz, 2H), 2.43−2.29 (m, 2H), 0.99 (t, J = 7.24, 1H); HPLC analysis: 44% ee, Chiral HPLC using Chiralpak 1A, (Hexane/IPA/TFA: 85/15/0.1), flow rate 1.0 mL/min, tR = 5.82 (minor) and 6.001 min (major). (R)-5-Nitro-4-phenyl-pentan-2-one (7e).20b White solid (201 mg, 97% yield); [α]D25 = −0.70 (c 1.0, CHCl3) [lit. [α]D25 = +3.5 (c 1.0, CHCl3, 84% ee)]; 1H NMR (400 MHz, CDCl3) δ 7.34−7.26 (m, 3H), 7.21−7.12 (m, 2H), 4.68 (dd, J = 6.84 and 12.32 Hz, 1H), 4.58 (dd, J = 7.68 and 12.32 Hz, 1H), 4.01−3.98 (m, 1H), 2.91 (d, J = 7.0 Hz, 2H), 2.11 (s, 3H); HPLC analysis: 25% ee, Chiral HPLC using Chiralpak 1A, (Hexane/IPA/TFA: 85/15/0.1), flow rate 1.0 mL/min, tR = 6.43 (minor) and 6.73 min (major). (4S,5R)-4-Methyl-6-nitro-5-phenyl-hexan-3-one (7f).13i Light brown liquid (35 mg, 15% yield); [α]D25 = +3.5 (c 0.56, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.33−7.26 (m, 3H), 7.15 (d, J = 7.32 Hz, 2H), 4.69−4.57 (m, 2H), 3.69−3.67 (m, 1H), 3.0−2.95 (m, 1H), 2.62−2.56 (m, 1H), 2.43−2.37 (m, 1H), 1.06 (t, J = 7.24 Hz, 3H), 0.96 (d, J = 7 Hz, 3H); HPLC analysis: 84% ee, Chiral HPLC using Chiralpak 1A (Hexane/EtOH/IPA: 80/20/0.1), flow rate 1.0 mL/ min, tR = 5.302 (minor) and 6.33 min (major). (2S,3R)-2-Methyl-4-nitro-3-phenyl-butyraldehyde (7g).20g Colorless liquid (128 mg, 62% yield); [α]D25 = +9.27 (c 0.46, CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.71 (s, 0.84 H, syn- isomer), 9.53 (s, 0.25 H, anti-isomer), 7.33−7.24 (m, 3H), 7.20−7.15 (m, 2H), 4.81− 4.76 (m, 1H), 4.70−4.64 (m, 1H), 4.54−4.49 (m, 0.45H, antiisomer), 3.94 (br s, 0.23 H, anti-isomer), 3.82−3.77 (m, 1H, synisomer), 3.15 (br s, 0.24 H, anti-isomer), 2.80−2.74 (m, 1H, synisomer), 1.21 (d, J = 7.12 Hz, 0.77H, anti-isomer), 0.99 (d, J = 8.24 Hz, 2.46 H, syn- isomer); HPLC analysis: 46% ee, Chiral HPLC using Chiralcel OD-H, EtOH, flow rate 0.3 mL/min, tR = 11.51 (major) and 12.15 min (minor). 1-[(3R,3aS,7aR/S)-3-(4-Trifluoromethyl-phenyl)-octahydro-indol1-yl]-ethanone (10). To a solution of 5e (140 mg, 0.52 mmol) in methanol (5 mL), 20% Pd(OH)2/C was added, and the resulting mixture was stirred at room temperature for 16 h under hydrogen atmosphere. After completion of the reaction, the reaction mixture was filtered through Celite bed, and then excess methanol (10 mL) was added for washing. The filtrate was concentrated under reduced pressure to give the crude product, which was dissolved in dichloromethane (5 mL), cooled to 0 °C, and treated with triethyl amine (0.21 mL, 1.56 mmol) followed by acetyl chloride (0.074 mL, 1.04 mmol). Then the reaction mixture was stirred at room temperature for 16 h. After aqueous work up, the organic part was concentrated in vacuo and purified by silica gel column chromatography to afford 74 mg (45% overall yield from 5e) of 10. [α]D25 = −23.46 (c 0.17, CHCl3); 1H NMR at 100 °C (400 MHz, DMSO-d6) [two isomers (3:1, according to HPLC, LC−MS)] δ 7.66 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 7.8 Hz, 2H), 3.92−3.90 (br d, J = 8.16 Hz, 1H), 3.50−3.40 (m, 2H), 3.15−2.96 (m, 2H), 1.96 (s, 3H), 1.78−1.56 (m, 4H), 1.42−1.18 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3, for major isomer) δ 170.6, 168.6, 143.2, 143.1, 129.5 (q, J = 32.34 Hz), 128.3, 127.9, 125.7, 124.1 (q, J = 270.10 Hz), 64.6, 64.3, 55.6, 52.5, 48.1, 31.6, 27.6, 25.8, 24.7; 19F NMR (376 MHz, CDCl3) δ −62.46 and −62.49 (s, 3F); LC−MS (ESI) 312.2 [M + H]+; HRMS (ESITOF) m/z [M + H]+ calcd for C17H21F3NO 312.1576, found 312.1601.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Mrinalkanti Kundu: 0000-0002-0907-6699 Animesh Pramanik: 0000-0002-0308-7186 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS CKM sincerely thanks TCGLS for providing the opportunity to carry out this research work and Dr. Subho Roy for valuable discussion. SM thanks UGC, New Delhi, India for offering Senior Research Fellowship (SRF). CKM and MK gratefully acknowledge the research collaboration with CU.

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REFERENCES

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H, 13C NMR, and LC−MS spectra of compounds (PDF) 1061

DOI: 10.1021/acs.joc.8b02393 J. Org. Chem. 2019, 84, 1053−1063

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