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DOI: 10.1055/s-0035-1561468
Asymmetric Synthesis of Tetrahydrobenzofurans and Annulated Dihydropyrans via Cooperative One-Pot Organo- and Silver-Catalysis
Publication History
Received: 29 April 2016
Accepted: 02 May 2016
Publication Date:
23 June 2016 (online)
In memory of Professor Jean Normant
Abstract
A low catalyst loading of a squaramide (0.5 mol%) and a silver(I) salt (1 mol%) efficiently catalyzes a one-pot asymmetric Michael addition/hydroalkoxylation reaction between 1,3-diketones and alkyne-tethered nitroalkenes. Depending on the 1,3-dicarbonyl substrate this cooperative catalytic approach opens access to tetrahydrobenzofurans or annulated dihydropyrans in moderate to excellent yields and very good to excellent enantioselectivities.
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Key words
asymmetric synthesis - organocatalysis - one-pot synthesis - silver catalysis - annulationBenzofuran and its partially hydrogenated analogues are important heterocyclic building blocks and very common structures in natural products with interesting biological and pharmaceutical properties. This is also true for structurally isomeric annulated dihydropyrans.[1] Natural products such as the furanomonoterpene evodone (I), which has been isolated from Evodia hortensis, exhibits significant inhibitory activity on the seed germination of certain species.[2] Curzerenone (II) and bisabolangelone (III) are other natural products with antibacterial and anti-inflammatory activities,[3] [4] respectively, whereas the diterpenoid maoecrystal V (IV) is a potent selective HeLa cell inhibitor.[5] The dihydropyran-type natural product crolibulin (V) and the pharmaceutical HA14-1 (VI) show anticancer properties (Figure [1]).[6]
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Recently, much effort has been invested in the synthesis of tetrahydrobenzofuran and dihydropyran core structures.[7] Singh and co-workers developed a silver-catalyzed interrupted Feist–Bénary reaction between ynones and β-diketones to provide dihydrofurans in moderate to good yields and good to excellent enantioselectivities (Scheme [1]).[8] Feng and co-workers reported an asymmetric domino Michael addition/O-alkylation reaction between cyclohexane-1,3-dione derivatives and bromonitrostyrenes catalyzed by a bifunctional N,N′-dioxide organocatalyst to afford polysubstituted bicyclic dihydrofurans.[9] Calter’s group published another interesting synthesis of highly substituted furanoids via an organocatalytic asymmetric aldol/oxa-Michael addition sequence between 2-ene-1,4-diketones and dimedone in the presence of a bis(cinchona alkaloid)-pyrimidine catalyst.[10] The Schneider group developed an interesting enantioselective phosphoric acid-catalyzed synthesis of 4-aryl-4H-chromenes via a conjugate addition of 1,3-diketones to in situ generated ortho-quinone methides followed by a cyclodehydration reaction.[11]
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The activation of alkynes for subsequent transformations has become an important tool in organic chemistry to develop new and valuable reactions. Alkyne functionalization can be achieved in two crucial routes: σ-activation (σ-bond metathesis or σ-coordination) and π-activation (π-complex formation).[12] The coinage metals (Cu, Ag and Au) are suitable candidates for alkyne functionalization due to their good alkynophilicity.[13] Especially, silver(I) salts have emerged as powerful activators of alkynes. The advantages of stability, nontoxicity, low price, or catalyst compatibility with organocatalysts favor the choice of silver in C≡C bond activation reactions such as alkynylation, cycloaddition, cycloisomerization, or hydrofunctionalization.[14]
Merging organocatalysis and metal catalysis enables multiple unique transformations in one-pot and this catalytic approach has become a powerful strategy in asymmetric synthesis. Particularly cooperative, relay, synergistic, and dual catalysis variations, where all reactants and catalysts are present from the beginning, is challenging and require high compatibility of the combined catalysts.[15]
In search of new methods for acquiring valuable bioactive heterocyclic compounds and our interest in the combination of organocatalysts and silver(I) salts,[16] we investigated an asymmetric Michael addition/hydroalkoxylation sequence between 1,3-diketones and alkyne-tethered nitroalkenes catalyzed by a bifunctional squaramide[17] and a silver(I) salt to provide the desired tetrahydrobenzofurans. We began our investigation by choosing dimedone (1) and nitroalkene 2a as model substrates. To our delight, the one-pot reaction of 1 and 2a in CH2Cl2 at room temperature catalyzed by squaramide A and Ag2O afforded the desired 5-exo-dig cyclization product 3a in 98% yield and 94% enantiomeric excess (Scheme [2]). Inspired by these excellent results, the reaction was carried out with different squaramide and thiourea catalysts A–I along with Ag2O as silver(I) salt. All squaramide catalysts as well as thiourea catalysts provided the tetrahydrobenzofuran in high yields and moderate to very good enantioselectivities. The best result was obtained with squaramide A, which gave 98% yield and 94% ee.
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The reaction conditions were optimized further by varying the solvent (Table [1]). The solvent screening indicated that the chlorinated solvents and Et2O gave very good results. The best yields were obtained with CH2Cl2 and CHCl3. We chose CH2Cl2 over CHCl3 on the basis of its lower toxicity. Further optimization studies were carried out by screening transition metal catalysts for the hydroalkoxylation reaction. Ag2CO3 provided the annulated product with 99% yield and 95% ee. The cost aspect led to our decision to use Ag2O instead of Ag2CO3. After carrying out the reaction at different temperatures and catalyst loadings of the squaramide and the silver(I) salt, we determined the optimal reaction conditions, these being 0.5 mol% of the squaramide A, 1 mol% of Ag2O, and CH2Cl2 as solvent at room temperature.
a Reaction conditions: Dimedone (1; 0.25 mmol), nitroalkene 2a (1.1 equiv), cat. A (1 mol%), Ag2O (10 mol%), solvent (2.5 mL, 0.1 M).
b Yield of 3a after flash chromatography.
c The enantiomeric excess was determined by HPLC on a chiral stationary phase.
d The reaction was carried out with A (0.5 mol%).
e The reaction was carried out with Ag2O (5 mol%) and A (0.5 mol%).
f The reaction was carried out with Ag2O (1 mol%) and A (0.5 mol%).
g The reaction was carried out with Ag2O (1 mol%) and A (0.5 mol%) at 0 °C.
The substrate scope of the cooperative organo- and silver-catalyzed asymmetric one-pot reaction was then explored for the reaction of dimedone (1) with various alkyne-tethered nitroalkenes 2 under optimal reaction conditions (Table [2]). The nitroalkenes with electron-withdrawing and electron–donating groups worked smoothly under the cooperative catalysis condition to provide tetrahydrobenzofurans 3b–f in excellent yields and very good enantioselectivities. The sterically encumbered 1-naphthyl- and 2-naphthyl-substituted nitroalkenes led to the formation of the desired tetrahydrobenzofurans 3g,h in very good yields and excellent enantiomeric excesses (Table [2]). Furthermore, the one-pot Michael addition/hydroalkoxylation sequence with heteroaryl-substituted nitroalkenes provided the desired annulated product 3i in excellent yields and enantioselectivity.
a Reaction conditions: Dimedone (1; 0.25 mmol), nitroalkene 2 (1.1 equiv), cat. A (0.5 mol%), Ag2O (1 mol%), solvent (2.5 mL, 0.1 M).
b Yield of 3a after flash chromatography.
c The enantiomeric excess was determined by HPLC on a chiral stationary phase.
An extended substrate scope was investigated using different cyclic 1,3-diketones based on five- and six-membered rings. The reaction with 1,3-cyclohexanedione led to the tetrahydrobenzofuran product in good yield and excellent enantioselectivity (Scheme [3, 5a]) Interestingly, a dihydropyran derivative 5b could be obtained in moderate yield and good enantiomeric excess using 1,3-cyclopentanedione. The substrate scope of the cooperative catalytic reaction was extended further to 1,3-diketones bearing heteroatoms, which also provided dihydropyran derivatives in moderate to very good yields and high enantioselectivities (Scheme [3, 5c, d]).
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The developed one-pot asymmetric transformation was also conducted with various 5-substituted 1,3-cyclohexanediones to introduce another stereocenter via desymmetrization. The desired tetrahydrobenzofurans could be obtained in very good yields and enantioselectivities, but the diastereomeric ratio was virtually 1:1 in all attempts (Scheme [4, 7a–d]).
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To evaluate the efficiency and synthetic utility of the current Michael addition/hydroalkoxylation strategy, tetrahydrobenzofuran 3a was prepared on a gram-scale maintaining the excellent yield and ee value (Scheme [5]).
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The absolute configuration of the tetrahydrobenzofurans was determined by X-ray crystal structure analysis of compound 5a (Figure [2])[18] in combination with a CD measurement and calculation (Figure [3]).
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The absolute configuration of the dihydropyran derivatives is based on an X-ray crystallographic analysis of compound 5d (Figure [4]).[18]
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This one-pot Michael addition/hydroalkoxylation protocol is proposed to proceed via two catalytic cycles (Scheme [6]). The first organocatalytic cycle involves the synergistic activation of the 1,3-diketone 1 and the nitroalkene 2 by the bifunctional squaramide A, where the squaramide moiety activates the nitroalkene 2 through the formation of hydrogen bonds to the nitro group and simultaneously the 1,3-diketone undergoes activation by the tertiary amine to promote the Michael addition from the Re-face. In the second catalytic cycle the silver forms a π-complex for the electrophilic activation of the internal alkyne to facilitate a 5-exo-dig or a 6-endo-dig annulation reaction leading to the vinylsilver intermediate. The latter undergoes a fast protodeargentation to provide the desired product 3, 5 and 7.
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In conclusion, we have developed a one-pot asymmetric Michael addition/hydroalkoxylation protocol by merging a bifunctional squaramide and a silver(I) salt at a very low catalyst loading. The combination of both catalytic systems enabled the formation of the desired tetrahydrobenzofurans and annulated dihydropyranes in moderate to excellent yields and good to excellent enantiomeric excesses.
Unless otherwise noted, all commercially available chemicals were used without purification. All solvents were distilled and purified according to standard procedures. Analytical TLC was performed using SIL G-25 UV252 from Macherey & Nagel (particle size 0.040–0.063 nm; 230–240 mesh. flash) and visualized with ultraviolet radiation at 254 nm. 1H, 13C, and 19F NMR spectra were recorded at ambient temperature on a Varian Innova 400 or Innova 600 spectrometer. Chemical shifts for 1H NMR and 13C NMR spectra are reported in parts per million (ppm) and coupling constants in hertz (Hz). Standard abbreviations are used for the spin multiplicity (qi = quintet). Optical rotations were measured on a PerkinElmer 241 polarimeter. Melting points were measured on a LLG MPM-H2 melting point instrument. Mass spectra were acquired on a Finnigan SSQ7000 (EI, 70 eV) spectrometer and on a ThermoFinnigan LCQ Deca XP plus (ESI) spectrometer and high-resolution ESI spectra on a ThermoFisher Scientific LTQ Orbitrap XL. Analytical HPLC was performed on a Aligent 1100, Aligent 1260, or Hewlett-Packard 1100 Series instrument using chiral stationary phases (Daicel Chiralpak IC, Daicel Chiralpak IA, Daicel Chiralpak AD, Daicel Chiralpak AS, Daicel Chiralpak IB columns). Analytical SFC was performed on a THAR-SFC MethodStation II with a WATERS 2998 Photodiode Array Detector using chiral stationary phases (Daicel Chiralcel OJ-H). Catalyst A and B,[19] D–I [20] and the nitroalkenes 2 [16c] were prepared according to known procedures.
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Tetrahydrobenzofurans and Annulated Dihydropyrans; General Procedure
A mixture of 1,3-diketones 1,4, or 6 (0.25 mmol), nitroalkene 2 (0.275 mmol, 1.1 equiv), catalyst A (0.5 mol%), and Ag2O (1 mol%) in CH2Cl2 (2.5 mL, 0.1 M) was stirred at r.t. until the intermediate Michael adduct was completely converted as indicated by TLC. The crude product was directly subjected to flash chromatography on silica (n-pentane/Et2O or n-pentane/CH2Cl2) to afford the corresponding product 3, 5, or 7.
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(R)-(Z)-2-Benzylidene-6,6-dimethyl-3-(nitromethyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one (3a)
Compound 3a was isolated after flash chromatography (n-pentane/Et2O, 1:1); yield: 75 mg (96%); colorless solid; mp 136–138 °C; Rf = 0.22 (n-pentane/Et2O, 1:1); [α]D 24 +96.6 (c = 0.6, MeOH).
HPLC: Daicel Chiralpak IC, n-heptane/i-PrOH (7:3), 1.0 mL/min, λ = 254 nm, t R (minor) = 7.6 min, t R (major) = 6.4 min; 96% ee.
IR (ATR): 2955, 2330, 2086, 1900, 1645, 1546, 1492, 1397, 1335, 1286, 1219, 1174, 1140, 1092, 998, 917, 849, 755, 694 cm–1.
1H NMR (600 MHz, C6D6): δ = 7.52 (d, J = 7.4 Hz, 2 H, ArH), 7.19 (t, J = 7.8 Hz, 2 H, ArH), 7.04 (t, J = 7.4 Hz, 1 H, ArH), 5.42 (d, J = 2.0 Hz, 1 H, OC=CH), 4.36 (dd, J = 13.1, 6.3 Hz, 1 H, CHHNO2), 4.17 (dd, J = 13.1, 4.7 Hz, 1 H, CHHNO2), 3.92 (s, 1 H, CHCH2), 1.93 (d, J = 16.0 Hz, 1 H, CH2), 1.85 (d, J = 16.0 Hz, 1 H, CH2), 1.66 (d, J = 17.9 Hz, 1 H, CH2), 1.58 (d, J = 17.9 Hz, 1 H, CH2), 0.64 (s, 3 H, CH3), 0.58 (s, 3 H, CH3).
13C NMR (151 MHz, C6D6): δ = 191.6 (C=O), 173.4 (Cq), 153.4 (Cq), 133.9 (Cq), 128.7 (2 C, ArC), 128.3 (2 C, ArC), 127.0 (ArC), 111.1 (Cq), 106.0 (OC=CH), 75.3 (CH2NO2), 50.5 (CH2), 41.9 (CHCH2), 36.1 (CH2), 33.2 [C(CH3)2], 28.4 (CH3), 27.2 (CH3).
MS (EI, 70 eV): m/z (%) = 313.1 (1, [M]+), 267.1 (17, [M – NO2]+), 253.0 (7, [M – CH2NO2]+), 90.1 (38, [CH2C6H5]+), 77.1 (27, [C6H5]+).
HRMS (ESI+): m/z [M + Na]+ calcd for C18H19NO4Na: 336.1206; found: 336.1195.
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(R)-(Z)-2-(3-Methoxybenzylidene)-6,6-dimethyl-3-(nitromethyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one (3b)
Compound 3b was isolated after flash chromatography (n-pentane/Et2O, 2:1); yield: 84 mg (98%); colorless solid; mp 127–129 °C; Rf = 0.17 (n-pentane/Et2O, 1:1); [α]D 24 +67.7 (c = 0.4, benzene).
HPLC: Daicel Chiralpak IC, n-heptane/i-PrOH (7:3), 0.7 mL/min, λ = 254 nm, t R (minor) = 14.0 min, t R (major) = 15.4 min; 96% ee.
IR (ATR): 2934, 2293, 2090, 1891, 1649, 1566, 1399, 1232, 1015, 840, 692 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.25 (m, 1 H, ArH), 7.11 (m, 2 H, ArH), 6.83–6.78 (m, 1 H, ArH), 5.71 (d, J = 2.2 Hz, 1 H, OC=CH), 4.89 (dd, J = 13.3, 3.9 Hz, 1 H, CHHNO2), 4.73 (dd, J = 13.3, 7.1 Hz, 1 H, CHHNO2), 4.58–4.53 (m, 1 H, CHCH2), 3.82 (s, 3 H, OCH3), 2.54 (m, 2 H, CH2), 2.31 (m, 2 H, CH2), 1.17 (s, 3 H, CH3), 1.16 (s, 3 H, CH3).
13C NMR (151 MHz, CDCl3): δ = 193.6 (C=O), 175.0 (Cq), 159.6 (Cq), 153.3 (Cq), 134.5 (Cq), 129.4 (ArC), 121.3 (ArC), 114.2 (ArC), 112.8 (ArC), 111.3 (Cq), 106.7 (OC=CH), 75.7 (CH2NO2), 55.2 (OCH3), 51.0 (CH2), 41.7 (CHCH2), 37.2 (CH2), 34.4 [C(CH3)2], 29.0 (CH3), 28.3 (CH3).
MS (EI, 70 eV): m/z (%) = 343.3 (5, [M]+), 297.3 (34, [M – NO2]+), 283.3 (12, [M – CH2NO2]+).
HRMS (ESI+): m/z [M + Na]+ calcd for C19H21NO5Na: 366.1312; found: 366.1310.
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(R)-(Z)-2-(2-Chlorobenzylidene)-6,6-dimethyl-3-(nitromethyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one (3c)
Compound 3c was isolated after flash chromatography (n-pentane/Et2O, 1:1); yield: 84 mg (97%); colorless solid; mp 130–132 °C; Rf = 0.36 (n-pentane/Et2O, 1:1); [α]D 24= 115.8 (c = 0.5, benzene).
HPLC: Daicel Chiralpak IA, n-heptane/i-PrOH (7:3), 0.7 mL/min, λ = 230 nm, t R (minor) = 8.4 min, t R (major) = 9.0 min; 95% ee.
IR (ATR): 2956, 2314, 2084, 1648, 1552, 1396, 1284, 1214, 1017, 972, 852, 754, 692 cm–1.
1H NMR (600 MHz, C6D6): δ = 7.95 (dd, J = 7.9, 1.6 Hz, 1 H, ArH), 7.17 (dd, J = 8.1, 1.2 Hz, 1 H, ArH), 6.97 (m, 1 H, ArH), 6.73 (m, 1 H, ArH), 6.04 (d, J = 2.3 Hz, 1 H, OC=CH), 4.48 (dd, J = 13.2, 5.3 Hz, 1 H, CHHNO2), 3.99 (dd, J = 13.2, 3.6 Hz, 1 H, CHHNO2), 3.69 (s, 1 H, CHCH2), 1.92 (d, J = 16.0 Hz, 1 H, CH2), 1.83 (d, J = 16.0 Hz, 1 H, CH2), 1.67 (d, J = 17.9 Hz, 1 H, CH2), 1.57 (d, J = 17.9 Hz, 1 H, CH2), 0.64 (s, 3 H, CH3), 0.56 (s, 3 H, CH3).
13C NMR (151 MHz, C6D6): δ = 191.6 (C=O), 173.2 (Cq), 155.4 (Cq), 132.7 (Cq), 131.9 (Cq), 130.2 (ArC), 129.4 (ArC), 128.1 (ArC), 126.5 (ArC), 111.4 (Cq), 101.5 (OC=CH), 75.2 (CH2NO2), 50.5 (CH2), 42.0 (CHCH2), 36.1 (CH2), 33.2 [C(CH3)2], 28.4 (CH3), 27.2 (CH3).
MS (EI, 70 eV): m/z (%) = 348.3 (1, [M + H]+), 303.3 (7, [M – NO2, 37Cl]+), 301.2 (37, [M – NO2, 35Cl]+), 289.2 (2, [M – CH2NO2, 37Cl]+), 287.2 (6, [M – NO2, 35Cl]+).
HRMS (ESI+): m/z [M + Na]+ calcd for C18H18ClNO4Na: 370.0812; found: 370.0813.
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(R)-(Z)-6,6-Dimethyl-3-(nitromethyl)-2-[4-(trifluoromethyl)benzylidene]-3,5,6,7-tetrahydrobenzofuran-4(2H)-one (3d)
Compound 3d was isolated after flash chromatography (n-pentane/Et2O, 1:2); yield: 106 mg (93%); colorless solid; mp 54–56 °C; Rf = 0.14 (n-pentane/Et2O, 1:1); [α]D 24 +49.2 (c = 0.3, benzene).
HPLC: Daicel Chiralpak IC, n-heptane/i-PrOH (8:2), 1.0 mL/min, λ = 254 nm, t R (minor) = 7.9 min, t R (major) = 6.1 min; 94% ee.
IR (ATR): 2962, 1949, 1692, 1651, 1615, 1552, 1400, 1321, 1219, 1166, 1116, 1067, 1014, 917, 862, 834, 791, 758, 703 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.59 (m, 4 H, ArH), 5.76 (d, J = 2.2 Hz, 1 H, OC=CH), 4.90 (dd, J = 13.4, 3.9 Hz, 1 H, CHHNO2), 4.75 (dd, J = 13.4, 6.9 Hz, 1 H, CHHNO2), 4.55 (m, 1 H, CHCH2), 2.55 (m, 2 H, CH2), 2.31 (s, 2 H, CH2), 1.17 (s, 3 H, CH3), 1.16 (s, 3 H, CH3).
13C NMR (101 MHz, CDCl3): δ = 193.5 (C=O), 174.7 (Cq), 155.0 (Cq), 136.8 (Cq), 128.7 (3 C, ArC), 125.3 (2 C, ArC), 122.7 (CF3), 111.4 (Cq), 105.4 (OC=CH), 75.4 (CH2NO2), 51.0 (CH2), 41.9 (CHCH2), 37.2 (CH2), 34.4 [C(CH3)2], 28.9 (CH3), 28.2 (CH3).
19F NMR (376 MHz, CDCl3): δ = –62.61 (s).
MS (EI, 70 eV): m/z (%) = 382.3 (3, [M + H]+), 335.3 (29, [M – NO2]+), 321.2 (9, [M – CH2NO2]+).
HRMS (ESI+): m/z [M + Na]+ calcd for C19H18F3NO4Na: 404.1080; found: 404.1069.
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(R)-(Z)-6,6-Dimethyl-2-(3-methylbenzylidene)-3-(nitromethyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one (3e)
Compound 3e was isolated after flash chromatography (n-pentane/Et2O, 1:1); yield: 79 mg (97%); colorless solid; mp 138–140 °C; Rf = 0.26 (n-pentane/Et2O, 1:1); [α]D 24 +71.2 (c = 0.4, benzene).
HPLC: Daicel Chiralpak IB, n-heptane/i-PrOH (7:3), 0.7 mL/min, λ = 254 nm, t R (minor) = 11.0 min, t R (major) = 10.0 min; 95% ee.
IR (ATR): 2957, 2290, 2086, 1644, 1547, 1474, 1403, 1328, 1280, 1214, 1171, 1093, 1006, 891, 840, 781, 697 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.37 (d, J = 7.8 Hz, 1 H, ArH), 7.32 (s, 1 H, ArH), 7.23 (t, J = 7.7 Hz, 1 H, ArH), 7.06 (d, J = 7.5 Hz, 1 H, ArH), 5.70 (d, J = 2.2 Hz, 1 H, OC=CH), 4.89 (dd, J = 13.2, 3.9 Hz, 1 H, CHHNO2), 4.73 (dd, J = 13.3, 7.1 Hz, 1 H, CHHNO2), 4.55 (m, 1 H, CHCH2), 2.55 (m, 2 H, CH2), 2.35 (s, 3 H, CH3), 2.32 (m, 2 H, CH2), 1.17 (s, 3 H, CH3), 1.16 (s, 3 H, CH3).
13C NMR (151 MHz, CDCl3): δ = 193.6 (C=O), 175.1 (Cq), 152.8 (Cq), 138.0 (Cq), 133.2 (Cq), 129.4 (ArC), 128.4 (ArC), 128.2 (ArC), 125.7 (ArC), 111.3 (Cq), 106.9 (OC=CH), 75.7 (CH2NO2), 51.0 (CH2), 41.7 (CHCH2), 37.3 (CH2), 34.4 [C(CH3)2], 29.0 (CH3), 28.3 (CH3), 21.5 (ArCH3).
MS (EI, 70 eV): m/z (%) = 327.2 (2, [M]+), 328.2 (9, [M + H]+), 281.3 (26, [M – NO2]+), 267.3 (17, [M – CH2NO2]+).
HRMS (ESI+): m/z [M + Na]+ calcd for C19H21NO4Na: 350.1363; found: 350.1356.
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(R)-(Z)-2-(Benzo[d][1,3]dioxol-5-ylmethylene)-6,6-dimethyl-3-(nitromethyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one (3f)
Compound 3f was isolated after flash chromatography (n-pentane/Et2O, 1:2); yield: 87 mg (97%); colorless solid; mp 138–140 °C; Rf = 0.21 (n-pentane/Et2O, 1:1); [α]D 24 +72.8 (c = 0.4, benzene).
HPLC: Daicel Chiralpak IB, n-heptane/EtOH (7:3), 1.0 mL/min, λ = 254 nm, t R (minor) = 9.8 min, t R (major) = 13.8 min; 95% ee.
IR (ATR): 2960, 1650, 1549, 1493, 1398, 1292, 1239, 1097, 1027, 928, 875, 804, 697 cm–1.
1H NMR (600 MHz, C6D6): δ = 7.42 (m, 1 H, ArH), 6.72 (m, 1 H, ArH), 6.64 (m, 1 H, ArH), 5.36 (d, J = 2.1 Hz, 1 H, OC=CH), 5.27 (m, 2 H, OCH2O), 4.31 (dd, J = 12.9, 6.4 Hz, 1 H, CHHNO2), 4.18 (dd, J = 13.0, 3.8 Hz, 1 H, CHHNO2), 3.94 (s, 1 H, CHCH2), 1.92 (d, J = 16.0 Hz, 1 H, CH2), 1.84 (d, J = 16.0 Hz, 1 H, CH2), 1.56 (d, J = 17.9 Hz, 1 H, CH2), 1.48 (d, J = 17.9 Hz, 1 H, CH2), 0.63 (s, 3 H, CH3), 0.57 (s, 3 H, CH3).
13C NMR (151 MHz, C6D6): δ = 191.7 (C=O), 173.4 (Cq), 151.9 (Cq), 148.1 (Cq), 146.8 (Cq), 128.1 (Cq), 123.1 (ArC), 111.0 (Cq), 108.6 (ArC), 108.2 (ArC), 106.0 (OC=CH), 100.8 (OCH2O), 75.4 (CH2NO2), 50.5 (CH2), 41.8 (CHCH2), 36.0 (CH2), 33.1 [C(CH3)2], 28.3 (CH3), 27.2 (CH3).
MS (EI, 70 eV): m/z (%) = 358.3 (5, [M + H]+), 357.3 (17, [M]+), 311.3 (24, [M – NO2]+), 297.3 (28, [M – CH2NO2]+).
HRMS (ESI+): m/z [M + Na]+ calcd for C19H19NO6Na: 380.1105; found: 380.1094.
#
(R)-(Z)-6,6-Dimethyl-2-(naphthalen-2-ylmethylene)-3-(nitromethyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one (3g)
Compound 3g was isolated after flash chromatography (n-pentane/Et2O, 1:1 to 1:2); yield: 85 mg (94%); colorless solid; mp 133–135 °C; Rf = 0.24 (n-pentane/Et2O, 1:1); [α]D 24 +93.9 (c = 0.4, benzene).
HPLC: Daicel Chiralpak IA, n-heptane/i-PrOH (7:3), 0.7 mL/min, λ = 254 nm, t R (minor) = 11.1 min, t R (major) = 11.7 min; 97% ee.
IR (ATR): 2956, 2313, 2073, 2002, 1646, 1549, 1463, 1401, 1290, 1218, 1173, 1140, 1090, 1019, 900, 862, 821, 749, 699 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.94 (s, 1 H, ArH), 7.84–7.77 (m, 3 H, ArH), 7.72 (dd, J = 8.6, 1.7 Hz, 1 H, ArH), 7.50–7.43 (m, 2 H, ArH), 5.90 (d, J = 2.1 Hz, 1 H, OC=CH), 4.94 (dd, J = 13.3, 3.9 Hz, 1 H, CHHNO2), 4.77 (dd, J = 13.3, 7.2 Hz, 1 H, CHHNO2), 4.62 (m, 1 H, CHCH2), 2.60 (m, 2 H, CH2), 2.34 (s, 2 H, CH2), 1.19 (s, 3 H, CH3), 1.18 (s, 3 H, CH3).
13C NMR (151 MHz, CDCl3): δ = 193.6 (C=O), 175.0 (Cq), 153.3 (Cq), 133.4 (Cq), 132.4 (Cq), 130.9 (Cq), 128.1 (ArC), 128.0 (ArC), 127.8 (ArC), 127.6 (ArC), 126.5 (ArC), 126.3 (ArC), 126.1 (ArC), 111.4 (Cq), 106.9 (OC=CH), 75.7 (CH2NO2), 51.1 (CH2), 41.8 (CHCH2), 37.3 (CH2), 34.4 [C(CH3)2], 29.0 (CH3), 28.3 (CH3).
MS (EI, 70 eV): m/z (%) = 364.3 (2, [M + H]+), 363.3 (4, [M]+), 317.3 (27, [M – NO2]+), 303.3 (12, [M – CH2NO2]+).
HRMS (ESI+): m/z [M + Na]+ calcd for C22H21NO4Na: 386.1363; found: 386.1351.
#
(R)-(Z)-6,6-Dimethyl-2-(naphthalen-1-ylmethylene)-3-(nitromethyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one (3h)
Compound 3h was isolated after flash chromatography (n-pentane/Et2O, 1:1); yield: 82 mg (90%); colorless solid; mp 165–167 °C; Rf = 0.23 (n-pentane/Et2O, 1:1); [α]D 24 +110.1 (c = 0.4, benzene).
HPLC: Daicel Chiralpak IB, n-heptane/EtOH (7:3), 0.5 mL/min, λ = 230 nm, t R (minor) = 15.9 min, t R (major) = 16.9 min; 95% ee.
IR (ATR): 3056, 2959, 1648, 1550, 1398, 1294, 1218, 1172, 1141, 1089, 1019, 975, 915, 838, 780, 699 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.98 (d, J = 8.3 Hz, 1 H, ArH), 7.87–7.77 (m, 3 H, ArH), 7.56–7.46 (m, 3 H, ArH), 6.41 (d, J = 2.1 Hz, 1 H, OC=CH), 5.02 (dd, J = 13.1, 3.9 Hz, 1 H, CHHNO2), 4.83 (dd, J = 13.1, 7.2 Hz, 1 H, CHHNO2), 4.72–4.66 (m, 1 H, CHCH2), 2.48 (m, 2 H, CH2), 2.32 (m, 2 H, CH2), 1.16 (s, 3 H, CH3), 1.15 (s, 3 H, CH3).
13C NMR (151 MHz, CDCl3): δ = 193.6 (C=O), 175.2 (Cq), 154.2 (Cq), 133.6 (Cq), 131.1 (Cq), 129.4 (Cq), 128.6 (ArC), 128.1 (ArC), 127.1 (ArC), 126.4 (ArC), 125.9 (ArC), 125.3 (ArC), 123.8 (ArC), 111.5 (Cq), 103.5 (OC=CH), 76.0 (CH2NO2), 51.0 (CH2), 41.7 (CHCH2), 37.2 (CH2), 34.4 [C(CH3)2], 29.0 (CH3), 28.3 (CH3).
MS (EI, 70 eV): m/z (%) = 364.4 (2, [M + H]+), 363.3 (7, [M]+), 317.3 (24, [M – NO2]+), 303.3 (6, [M – CH2NO2]+).
HRMS (ESI+): m/z [M + Na]+ calcd for C22H21NO4Na: 386.1323; found: 386.1345.
#
(R)-(Z)-2-(Furan-2-ylmethylene)-6,6-dimethyl-3-(nitromethyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one (3i)
Compound 3i was isolated after flash chromatography (n-pentane/Et2O, 1:1); yield: 73 mg (96%); colorless solid; mp 103–105 °C; Rf = 0.31 (n-pentane/Et2O, 1:1); [α]D 24 +85.7 (c = 0.4, benzene).
HPLC: Daicel Chiralpak IB, n-heptane/EtOH (7:3), 0.7 mL/min, λ = 254 nm, t R (minor) = 9.3 min, t R (major) = 10.3 min; 96% ee.
IR (ATR): 2960, 2876, 2081, 1988, 1649, 1554, 1466, 1374, 1292, 1228, 1167, 1089, 1049, 1016, 989, 920, 884, 816, 747, 700, 671 cm–1.
1H NMR (600 MHz, C6D6): δ = 7.05 (d, J = 1.6 Hz, 1 H, OCH), 6.59 (d, J = 3.3 Hz, 1 H, CH), 6.19 (dd, J = 3.3, 1.8 Hz, 1 H, CH), 5.61 (d, J = 2.3 Hz, 1 H, OC=CH), 4.29 (dd, J = 13.2, 6.1 Hz, 1 H, CHHNO2), 4.04 (dd, J = 13.2, 3.7 Hz, 1 H, CHHNO2), 3.79 (s, 1 H, CHCH2), 1.90 (d, J = 16.0 Hz, 1 H, CH2), 1.82 (d, J = 16.0 Hz, 1 H, CH2), 1.71 (d, J = 17.8 Hz, 1 H, CH2), 1.63 (d, J = 17.8 Hz, 1 H, CH2), 0.62 (s, 3 H, CH3), 0.57 (s, 3 H, CH3).
13C NMR (151 MHz, C6D6): δ = 191.6 (C=O), 173.2 (Cq), 152.1 (Cq), 149.1 (Cq), 141.2 (OCH), 111.6 (CH), 111.3 (Cq), 109.5 (CH), 96.2 (OC=CH), 74.8 (CH2NO2), 50.5 (CH2), 41.4 (CHCH2), 36.2 (CH2), 33.2 [C(CH3)2], 28.3 (CH3), 27.2 (CH3).
MS (EI, 70 eV): m/z (%) = 304.1 (1, [M + H]+), 303.1 (5, [M]+), 257.1 (24, [M – NO2]+), 243.0 (13, [M – CH2NO2]+).
HRMS (ESI+): m/z [M + Na]+ calcd for C16H17NO5Na: 326.0999; found: 326.0990.
#
(R)-(Z)-2-Benzylidene-3-(nitromethyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one (5a)
Compound 5a was isolated after flash chromatography (n-pentane/Et2O, 1:2); yield: 56 mg (79%); colorless solid; mp 117–119 °C; Rf = 0.14 (n-pentane/Et2O, 1:1); [α]D 24 +74.9 (c = 0.5, benzene).
HPLC: Daicel Chiralpak AS, n-heptane/EtOH (7:3), 0.7 mL/min, λ = 254 nm, t R (minor) = 13.3 min, t R (major) = 15.9 min; 98% ee.
IR (ATR): 2953, 2322, 2087, 1892, 1641, 1547, 1384, 1217, 1176, 1051, 974, 841, 696 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.54 (d, J = 7.4 Hz, 2 H, ArH), 7.34 (t, J = 7.8 Hz, 2 H, ArH), 7.24 (t, J = 7.4 Hz, 1 H, ArH), 5.73 (d, J = 2.1 Hz, 1 H, OC=CH), 4.92 (dd, J = 13.2, 3.8 Hz, 1 H, CHHNO2), 4.67 (dd, J = 13.2, 7.6 Hz, 1 H, CHHNO2), 4.58 (m, 1 H, CHCH2), 2.72–2.65 (m, 2 H, CH2), 2.47–2.42 (m, 2 H, CH2), 2.16 (qi, J = 6.4 Hz, 2 H, CH2).
13C NMR (151 MHz, CDCl3): δ = 194.1 (C=O), 176.0 (Cq), 152.8 (Cq), 133.3 (Cq), 128.7 (ArC), 128.5 (ArC), 127.3 (ArC), 112.7 (Cq), 106.8 (OC=CH), 75.9 (CH2NO2), 41.7 (CHCH2), 36.6 (CH2), 23.4 (CH2), 21.5 (CH2).
MS (EI, 70 eV): m/z (%) = 286.3 (13, [M + H]+), 285.2 (2, [M]+), 239.3 (21, [M – NO2]+), 225.2 (19, [M – CH2NO2]+).
HRMS (ESI+): m/z [M + Na]+ calcd for C16H15NO4Na: 308.0893; found: 308.0893.
#
(R)-4-(Nitromethyl)-2-phenyl-6,7-dihydrocyclopenta[b]pyran-5(4H)-one (5b)
Compound 5b was isolated after flash chromatography (n-pentane/Et2O, 1:2); yield: 43 mg (63%); colorless solid; mp 153–155 °C; Rf = 0.19 (n-pentane/Et2O, 1:1); [α]D 24 –162.9 (c = 0.4, benzene).
HPLC: Daicel Chiralpak IC, n-heptane/EtOH (7:3), 0.7 mL/min, λ = 230 nm, t R (minor) = 10.7 min, t R (major) = 8.8 min; 94% ee.
IR (ATR): 3075, 2922, 2308, 2096, 1902, 1665, 1543, 1393, 1234, 991, 856, 764, 696 cm–1.
1H NMR (600 MHz, C6D6): δ = 7.32 (m, 2 H, ArH), 7.04 (m, 3 H, ArH), 5.09 (d, J = 3.6 Hz, 1 H, OC=CH), 4.20 (m, 2 H, CH2NO2), 3.47 (m, 1 H, CHCH2), 1.89 (ddd, J = 17.8, 7.4, 2.8 Hz, 1 H, CH), 1.81 (ddd, J = 17.9, 7.4, 2.5 Hz, 1 H, CH), 1.75 (m, 1 H, CH), 1.68 (m, 1 H, CH).
13C NMR (151 MHz, C6D6): δ = 200.7 (C=O), 179.2 (Cq), 150.7 (Cq), 132.3 (Cq), 129.2 (ArC), 128.4 (2 C, ArC), 124.9 (2 C, ArC), 111.8 (Cq), 98.7 (OC=CH), 76.6 (CH2NO2), 32.8 (CH2), 29.8 (CHCH2), 24.9 (CH2).
MS (EI, 70 eV): m/z (%) = 272.2 (3, [M + H]+), 225.2 (27, [M – NO2]+), 211.2 (84, [M – CH2NO2]+).
HRMS (ESI+): m/z [M + Na]+ calcd for C15H13NO4Na: 294.0737; found: 294.0732.
#
(R)-4-(Nitromethyl)-2-phenyl-4,8-dihydropyrano[3,4-b]pyran-5(6H)-one (5c)
Compound 5c was isolated after flash chromatography (n-pentane/Et2O, 1:1 to 1:2); yield: 22 mg (31%); colorless solid; mp 113–115 °C; Rf = 0.43 (n-pentane/Et2O, 1:1); [α]D 24 –213.5 (c = 0.4, benzene).
HPLC: Daicel Chiralpak IA, n-heptane/i-PrOH (7:3), 0.7 mL/min, λ = 254 nm, t R (minor) = 14.2 min, t R (major) = 11.9 min; 90% ee.
IR (ATR): 2962, 1675, 1635, 1546, 1494, 1439, 1393, 1270, 1229, 1139, 1056, 994, 952, 873, 814, 764, 677 cm–1.
1H NMR (600 MHz, C6D6): δ = 7.22–7.19 (m, 2 H, ArH), 7.05–7.02 (m, 3 H, ArH), 5.10 (d, J = 4.3 Hz, 1 H, OC=CH), 4.06 (dd, J = 11.7, 7.0 Hz, 1 H, CHHNO2), 4.01 (dd, J = 11.7, 3.8 Hz, 1 H, CHHNO2), 3.92 (d, J = 15.9 Hz, 1 H, CH2), 3.75 (d, J = 16.2 Hz, 1 H, CH2), 3.67–3.63 (m, 1 H, CHCH2), 3.59 (dd, J = 15.9, 1.7 Hz, 1 H, CH2), 3.52 (dd, J = 16.1, 1.4 Hz, 1 H, CH2).
13C NMR (151 MHz, C6D6): δ = 192.1 (C=O), 165.3 (Cq), 149.2 (Cq), 131.9 (Cq), 129.2 (ArC), 128.3 (ArC), 124.6 (ArC), 106.1 (Cq), 99.1 (OC=CH), 77.6 (CH2NO2), 71.1 (CH2), 63.5 (CH2), 28.4 (CHCH2).
MS (EI, 70 eV): m/z (%) = 241.1 (17, [M – NO2]+), 227.1 (45, [M – CH2NO2]+).
HRMS (ESI+): m/z [M + Na]+ calcd for C15H13NO5Na: 310.0686; found: 310.0686.
#
(R)-1,3-Dimethyl-5-(nitromethyl)-7-phenyl-1,5-dihydro-2H-pyrano[2,3-d]pyrimidine-2,4(3H)-dione (5d)
Compound 5d was isolated after flash chromatography [n-pentane/CH2Cl2 (1:4) to pure CH2Cl2]; yield: 77 mg (94%); bright yellow solid; mp 224–226 °C; Rf = 0.26 (CH2Cl2/Et2O, 20:1); [α]D 24 –144.5 (c = 0.4, CHCl3).
HPLC: Daicel Chiralpak AS, n-heptane/EtOH (7:3), 1.0 mL/min, λ = 254 nm, t R (minor) = 10.3 min, t R (major) = 7.5 min; 88% ee.
IR (ATR): 2954, 2324, 2107, 1645, 1476, 1375, 1203, 1003, 753, 690 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.58–7.52 (m, 2 H, ArH), 7.45–7.41 (m, 3 H, ArH), 5.71 (d, J = 4.4 Hz, 1 H, OC=CH), 4.83–4.74 (m, 2 H, CH2NO2), 4.24 (dt, J = 6.1, 4.3 Hz, 1 H, CHCH2), 3.54 (s, 3 H, CH3), 3.39 (s, 3 H, CH3).
13C NMR (151 MHz, CDCl3): δ = 162.0 (C=O), 154.3 (C=O), 150.5 (Cq), 149.7 (Cq), 131.2 (Cq), 130.0 (ArC), 128.8 (2 C, ArC), 124.8 (2 C, ArC), 99.2 (OC=CH), 84.0 (Cq), 77.9 (CH2NO2), 30.9 (CHCH2), 29.2 (CH3), 28.2 (CH3).
MS (EI, 70 eV) m/z (%) = 283.1 (20, [M – NO2]+), 269.0 (71, [M – CH2NO2]+).
HRMS (ESI+): m/z [M + Na]+ calcd for C16H15N3O5Na: 352.0904; found: 352.0894.
#
(R)-(Z)-2-Benzylidene-6-methyl-3-(nitromethyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one (7a)
Compound 7a was isolated after flash chromatography (n-pentane/Et2O, 1:1 to 1:2); yield: 73 mg (98%); colorless solid; mp 175–177 °C; Rf = 0.24 (n-pentane/Et2O, 1:1); [α]D 24 +85.5 (c = 0.5, MeOH).
HPLC: Daicel Chiralpak IC, n-heptane/i-PrOH (7:3), 0.5 mL/min, λ = 254 nm, t R (minor) 1 = 27.5 min, t R (major) 1 = 16.6 min; t R (minor) 2 = 29.9 min, t R (major) 2 = 18.2 min; 94% ee, dr = 1:1.
IR (ATR): 2951, 2925, 2871, 2153, 2086, 2048, 1989, 1735, 1691, 1650, 1549, 1389, 1288, 1205, 1163, 1099, 1016, 973, 914, 873, 847, 811, 752, 694 cm–1.
1H NMR (600 MHz, C6D6): δ = 7.51 (m, 4 H, ArH, ArHDiast.), 7.18 (m, 4 H, Ar-H, ArHDiast.), 7.03 (m, 2 H, ArH, ArHDiast.), 5.44 (d, J = 2.2 Hz, 1 H, OC=CH), 5.42 (d, J = 2.2 Hz, 1 H, OC=CHDiast.), 4.34 (dd, J = 13.1, 6.4 Hz, 1 H, CH2NO2), 4.28 (dd, J = 13.0, 6.6 Hz, 1 H, CH2NO2 Diast.), 4.22 (ddd, J = 13.0, 7.9, 3.8 Hz, 2 H, CH2NO2, CH2NO2 Diast.), 3.94 (m, 2 H, CHCH2, CHCH2 Diast.), 2.07 (m, 4 H, CH2, CH2 Diast.), 1.65 (m, 4 H, CH2, CH2 Diast.), 1.56 (m, 2 H, CHCH3, CHCH3 Diast.), 1.44 (m, 1 H, CHH), 1.27 (m, 1 H, CHH Diast.), 0.50 (d, J = 6.6 Hz, 3 H, CH3), 0.46 (d, J = 6.3 Hz, 3 H, CH3 Diast.).
13C NMR (151 MHz, C6D6): δ = 191.8 (C=O), 191.8 (C=ODiast.), 174.2 (Cq), 174.0 (Cq Diast.), 153.3 (Cq), 153.3 (Cq Diast.), 133.9 (Cq), 133.9 (Cq Diast.), 128.7 (4 C, ArC, ArCDiast.), 128.4 (4 C, ArC, ArCDiast.), 127.0 (2 C, ArC, ArCDiast.), 112.1 (Cq), 111.9 (Cq Diast.), 106.1 (OC=CH), 106.0 (OC=CHDiast.), 75.7 (CH2NO2), 75.1 (CH2NO2 Diast.), 44.6 (CH2), 44.5 (CH2 Diast.), 41.9 (CHCH2), 41.8 (CHCH2 Diast.), 30.3 (CH2), 30.2 (CH2 Diast.), 29.2 (CHCH3), 29.0 (CHCH3 Diast.), 20.1 (CH3), 12.0 (CH3 Diast.).
MS (EI, 70 eV): m/z (%) = 300.0 (3, [M + H]+), 253.1 (19, [M – NO2]+), 239.0 (11, [M – CH2NO2]+).
HRMS (ESI+): m/z [M + Na]+ calcd for C17H17NO4Na: 322.1050; found: 322.1049.
#
(R)-(Z)-2-Benzylidene-6-isopropyl-3-(nitromethyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one (7b)
Compound 7b was isolated after flash chromatography (n-pentane/Et2O, 1:1 to 1:2); yield: 67 mg (82%); colorless solid; mp 141–143 °C; Rf = 0.33 (n-pentane/Et2O, 1:1); [α]D 24 +52.7 (c = 0.5, benzene).
HPLC: Daicel Chiralpak IA, n-heptane/EtOH (97:3), 1.0 mL/min, λ = 254 nm, t R (minor) 1 = 41.7 min, t R (major) 1 = 63.8 min; t R (minor) 2 = 50.4 min, t R (major) 2 = 58.3 min; 93% ee, dr = 1:1.
IR (ATR): 3352, 2956, 2325, 2096, 1649, 1546, 1381, 1100, 958, 842, 756, 687 cm–1.
1H NMR (600 MHz, C6D6): δ = 7.53 (m, 4 H, ArH, ArH Diast.), 7.20 (m, 4 H, ArH, ArHDiast.), 7.05 (m, 2 H, ArH, ArHDiast.), 5.49 (d, J = 2.1 Hz, 1 H, OC=CH), 5.47 (d, J = 2.1 Hz, 1 H, OC=CHDiast.), 4.35 (m, 1 H, CHHNO2), 4.30 (m, 3 H, CH2NO2, CH2NO2 Diast.), 4.05 (m, 1 H, CHCH2), 4.01 (m, 1 H, CHCH2 Diast.), 2.17 (m, 2 H, CHH, CHHDiast.), 1.79 (m, 3 H, CHH, CHHDiast.), 1.59 [m, 2 H, CHCH(CH3)2, CHCH(CH3)2 Diast.], 1.43 (m, 2 H, CHH, CHH Diast.), 1.31 (m, 1 H, CHH), 1.01 [m, 2 H, CH(CH3)2, CH(CH3)2 Diast.], 0.48 [m, 12 H, CH(CH 3)2, CH(CH 3)2 Diast.].
13C NMR (151 MHz, C6D6): δ = 192.1 (C=O), 192.1 (C=O Diast.), 174.7 (Cq), 174.7 (Cq Diast.), 153.4 (Cq), 153.4 (Cq Diast.), 133.9 (Cq), 133.9 (Cq Diast.), 128.7 (4 C, ArC, ArCDiast.), 128.4 (4 C, ArC, ArCDiast.), 127.1 (2 C, ArC, ArC Diast.), 112.2 (Cq), 112.0 (Cq Diast.), 106.1 (OC=CH), 106.0 (OC=CHDiast.), 75.8 (CH2NO2), 75.1 (CH2NO2 Diast.), 41.9 (CHCH2), 41.9 (CHCH2 Diast.), 40.7 (CH2), 40.4 (CH2 Diast.), 40.3 [CHCH(CH3)2], 40.2 [CHCH(CH3)2 Diast.], 31.4 [CH(CH3)2], 31.3 [CH(CH3)2 Diast.], 26.1 (CH2), 25.9 (CH2 Diast.), 19.3 (CH3), 19.1 (CH3 Diast.), 18.8 (CH3), 18.7 (CH3 Diast.).
MS (EI+, 70 eV): m/z (%) = 328.1 (3, [M + H]+), 327.1 (1, [M]+), 281.1 (33, [M – NO2]+), 267.1 (8, [M – CH2NO2]+).
HRMS (ESI+): m/z [M + Na]+ calcd for C19H21NO4Na: 350.1363; found: 350.1362.
#
(R)-(Z)-2-Benzylidene-3-(nitromethyl)-6-phenyl-3,5,6,7-tetrahydrobenzofuran-4(2H)-one (7c)
Compound 7c was isolated after flash chromatography (n-pentane/Et2O, 1:1 to 1:2); yield: 85 mg (94%); colorless solid; mp 128–130 °C; Rf = 0.24 (n-pentane/Et2O, 1:1); [α]D 24 +64.8 (c = 0.5, benzene).
HPLC: Daicel Chiralpak AD, n-heptane/EtOH (1:1), 1.0 mL/min, λ = 254 nm, t R (minor) 1 = 9.2 min, t R (major) 1 = 17.1 min; t R (minor) 2 = 11.0 min, t R (major) 2 = 13.9 min; 94% ee, dr = 1:1.
IR (ATR): 3027, 2305, 2102, 1910, 1735, 1647, 1546, 1397, 1204, 1002, 909, 853, 753, 694 cm–1.
1H NMR (600 MHz, C6D6): δ = 7.51 (m, 4 H, ArH, ArHDiast.), 7.19 (m, 4 H, ArH, ArHDiast.), 7.04 (m, 8 H, ArH, Diast.), 6.72 (m, 4 H, ArH, ArHDiast.), 5.48 (s, 2 H, OC=CH, OC=CHDiast.), 4.32 (m, 4 H, CH2NO2, CH2NO2 Diast.), 4.06 (m, 1 H, CHCH2), 4.00 (m, 1 H, CHCH2 Diast.), 2.83 (m, 1 H, CHC6H5), 2.70 (m, 1 H, CHC6H5 Diast.), 2.36 (m, 2 H, CH2 Diast.), 2.23 (dd, J = 16.2, 12.5 Hz, 1 H, CHH), 2.11 (dd, J = 16.2, 12.9 Hz, 1 H, CHH), 1.92 (m, 4 H, CH2, CH2 Diast.).
13C NMR (151 MHz, C6D6): δ = 191.0 (C=O), 190.9 (C=ODiast.), 173.8 (Cq), 173.8 (Cq Diast.), 153.3 (Cq), 153.2 (Cq Diast.), 142.0 (Cq), 142.0 (Cq Diast.), 133.8 (Cq), 133.8 (Cq Diast.), 128.7 (4 C, ArC, ArCDiast.), 128.5 (4 C, ArC, ArCDiast.), 128.4 (4 C, ArC, ArCDiast.), 127.1 (2 C, ArC, ArCDiast.), 127.0 (2 C, ArC, ArCDiast.), 126.6 (4 C, ArC, ArCDiast.) 112.3 (Cq), 112.2 (Cq Diast.), 106.3 (OC=CH), 106.3 (OC=CHDiast.), 75.7 (CH2NO2), 75.0 (CH2NO2 Diast.), 43.7 (CH2), 43.6 (CH2 Diast.), 41.9 (CHCH2), 41.8 (CHCH2 Diast.), 39.7 (CHPh), 39.6 (CHPhDiast.), 30.1 (CH2), 30.0 (CH2 Diast.).
MS (EI+, 70 eV): m/z (%) = 361.1 (1, [M + H]+), 315.1 (38, [M – NO2]+), 301.1 (7, [M – CH2NO2]+).
HRMS (ESI+): m/z [M + Na]+ calcd for C22H19NO4Na: 384.1206; found: 384.1207.
#
(R)-(Z)-2-Benzylidene-6-(furan-2-yl)-3-(nitromethyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one (7d)
Compound 7d was isolated after flash chromatography (n-pentane/Et2O, 1:1); yield: 86 mg (98%); colorless solid; mp 143–145 °C; Rf = 0.21 (n-pentane/Et2O, 1:1); [α]D 24 +64.8 (c = 0.4, MeOH).
SFC: Daicel Chiralcel OJ-H, CO2/MeCN (8:2), 4.0 mL/min, λ = 222 nm, t R (minor) 1 = 3.9 min, t R (major) 1 = 5.2 min; t R (minor) 2 = 7.1 min, t R (major) 2 = 9.7 min; 99% ee, dr = 1:1.
IR (ATR): 2914, 2327, 2098, 1647, 1547, 1393, 1201, 1009, 849, 752 cm–1.
1H NMR (600 MHz, C6D6): δ = 7.47 (t, J = 6.9 Hz, 4 H, ArH, ArHDiast.), 7.17 (m, 4 H, ArH, ArHDiast.), 7.03 (m, 2 H, ArH, ArHDiast.), 6.96–6.93 (m, 2 H, OCH, OCHDiast.), 5.97 (ddd, J = 6.6, 3.2, 1.9 Hz, 2 H, ArH, ArHDiast.), 5.65 (d, J = 3.2 Hz, 2 H, ArH, ArHDiast.), 5.44 (d, J = 2.2 Hz, 1 H, OC=CH), 5.41 (d, J = 2.2 Hz, 1 H, OC=CHDiast.), 4.25 (m, 2 H, CHHNO2, CHHNO2 Diast.), 4.17 (m, 2 H, CHHNO2, CHHNO2 Diast.), 4.01 (m, 1 H, CHCH2), 3.89 (m, 1 H, CHCH2 Diast.), 2.88 (m, 1 H, CHAr), 2.82 (m, 1 H, CHArDiast.), 2.37 (m, 2 H, CH2, CH2 Diast.), 2.21 (m, 2 H, CH2, CH2 Diast.), 2.07 (m, 4 H, CH2, CH2 Diast.).
13C NMR (151 MHz, C6D6): δ = 190.2 (2 C, C=O, C=ODiast.), 172.9 (Cq), 172.8 (Cq Diast.), 155.1 (Cq), 155.0 (Cq Diast.), 153.1 (Cq), 153.0 (Cq Diast.), 141.4 (2 C, OCHfuranyl, OCHfuranyl, Diast.), 133.7 (Cq), 133.7 (Cq Diast.), 128.7 (4 C, ArC, ArCDiast.), 128.3 (4 C, ArC, ArCDiast.), 127.1 (2 C, ArC, ArCDiast.), 112.3 (Cq), 112.2 (Cq Diast.), 110.1 (CHfuranyl), 110.1 (CHfuranyl, Diast.), 106.3 (OC=CH), 106.3 (OC=CO Diast.), 104.9 (CHfuranyl), 104.8 (CHfuranyl, Diast.), 75.4 (CH2NO2), 75.0 (CH2NO2 Diast.), 41.8 (CHCH2), 41.7 (CHCH2 Diast.), 40.8 (CH2), 40.7 (CH2 Diast.), 33.0 (CHfuranyl), 32.8 (CHfuranyl, Diast.), 27.4 (2 C, CH2, CH2 Diast.).
MS (EI, 70 eV): m/z (%) = 351.1 (1, [M]+), 305.1 (44, [M – NO2]+), 291.1 (7, [M – CH2NO2]+).
HRMS (ESI+): m/z [M + Na]+ calcd for C20H17NO5Na: 374.0999; found: 374.0997.
#
#
No conflict of interest has been declared by the author(s).
Acknowledgment
Financial support from the European Research Council (ERC Advanced Grant 320493 ‘DOMINOCAT’) is gratefully acknowledged. We thank Prof. Englert, Institute of Inorganic Chemistry for his help with the X-ray crystal structure determination of 5a.
Supporting Information
- Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0035-1561468.
- Supporting Information
-
References
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- 14b Yamamoto Y. Chem. Rev. 2008; 108: 3199
- 14c Weibel J.-M. Blanc A. Pale P. Chem. Rev. 2008; 108: 3149
- 14d Álvarez-Corral M. Munoz-Dorado M. Rodríguez-García I. Chem. Rev. 2008; 108: 3174
- 14e Belmont P. Parker E. Eur. J. Org. Chem. 2009; 6075
- 14f Fang G. Bi X. Chem. Soc. Rev. 2015; 44: 8124
- 14g Sekine K. Yamada T. Chem. Soc. Rev. 2016; 45 DOI: in press; 10.1039/c5cs00895f.
- 15a Ding Q. Wu J. Org. Lett. 2007; 9: 4959
- 15b Shao Z. Zhang H. Chem. Soc. Rev. 2009; 38: 2745
- 15c Zhong C. Shi X. Eur. J. Org. Chem. 2010; 2999
- 15d Arróniz C. Gil-González A. Semak V. Escolano C. Bosch J. Amat M. Eur. J. Org. Chem. 2011; 3755
- 15e Loh CC. J. Enders D. Chem. Eur. J. 2012; 18: 10212
- 15f Du Z. Shao Z. Chem. Soc. Rev. 2013; 42: 1337
- 15g Deng Y. Kumar S. Wang H. Chem. Commun. 2014; 50: 4272
- 16a Hack D. Loh CC. J. Hartmann JM. Raabe G. Enders D. Chem. Eur. J. 2014; 20: 3917
- 16b Hack D. Chauhan P. Deckers K. Hermann GN. Mertens L. Raabe G. Enders D. Org. Lett. 2014; 16: 5188
- 16c Hack D. Chauhan P. Deckers K. Mizutani Y. Raabe G. Enders D. Chem. Commun. 2015; 51: 2266
- 16d Hack D. Dürr AB. Deckers K. Chauhan P. Seling N. Rübenach L. Mertens L. Raabe G. Schoenebeck F. Enders D. Angew. Chem. Int. Ed. 2016; 53: 1797
- 16e Kaya U. Chauchan P. Hack D. Deckers K. Puttreddy R. Rissanen K. Enders D. Chem. Commun. 2016; 52: 1669
- 17a Alemán J. Parra A. Jiang H. Jørgensen KA. Chem. Eur. J. 2011; 17: 6890
- 17b Storer RI. Aciro C. Jones LH. Chem. Soc. Rev. 2011; 40: 2330
- 17c Ni X. Li X. Wang Z. Cheng J.-P. Org. Lett. 2014; 16: 1786
- 17d Chauhan P. Mahajan S. Kaya U. Hack D. Enders D. Adv. Synth. Catal. 2015; 357: 253
- 18 CCDC 1474771 (5a) and CCDC 1474975 (5d) contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
- 19 Yang W. Du D.-M. Adv. Synth. Catal. 2011; 353: 1241
For examples of merging organo- and transition metal-catalysis, see:
-
References
- 1a Sainsbury M. In Heterocyclic Chemistry . Abel EW. The Royal Society of Chemistry; Cambridge: 2001: 58
- 1b Wolfe JP. Hay MB. Tetrahedron 2007; 63: 261
- 1c Miyabe H. Miyata O. Naito T. In Heterocycles in Natural Product Synthesis . Majumdar KC. Chattopadhyay SK. Wiley-VCH; Weinheim: 2011: 153
- 1d Lorente A. Lamariano-Merketegi J. Albericio F. Álvarez M. Chem. Rev. 2013; 113: 4567
- 1e Dar AM. Shamsuzzaman Eur. Chem. Bull. 2015; 4: 249
- 1f Kumar KA. Renuka N. Kumar GV. Lokeshwari DM. J. Chem. Pharm. Res. 2015; 7: 693
- 2a Juo R.-R. Herz W. J. Org. Chem. 1985; 50: 700
- 2b Srikrishna A. Krishnan K. Tetrahedron Lett. 1988; 29: 4995
- 2c Tanrisever N. Fischer NH. Williamson GB. Phytochemistry 1988; 27: 2523
- 2d Aso M. Qjida A. Yang G. Cha O.-J. Osawa E. Kanematsu K. J. Org. Chem. 1993; 58: 3960
- 2e Lee YR. Lee GJ. Kang KY. Bull. Korean Chem. Soc. 2002; 23: 1477
- 3 Joshi SC. Mathela CS. Pharmacog. Res. 2012; 4: 80
- 4 Jung HW. Mahesh R. Park JH. Boo YC. Park KM. Park Y.-K. Int. Immunopharmacol. 2010; 10: 155
- 5a Gong J. Lin G. Sun W. Li C.-C. Yang Z. J. Am. Chem. Soc. 2010; 132: 16745
- 5b Lu P. Mailyan A. Gu Z. Guptill DM. Wang H. Davies HM. L. Zakarian A. J. Am. Chem. Soc. 2014; 136: 17738
- 5c Zheng C. Dubovyk I. Lazarski KE. Thomson RJ. J. Am. Chem. Soc. 2014; 136: 17750
- 5d Zhang W.-B. Lin G. Shao W.-B. Gong J.-X. Yang Z. Chem. Asian J. 2015; 10: 903
- 5e Zhang W.-B. Shao W.-B. Li F.-Z. Gong J.-X. Yang Z. Chem. Asian J. 2015; 10: 1874
- 6a Adili A. Tao Z.-L. Chen D.-F. Han Z.-Y. Org. Biomol. Chem. 2015; 13: 2247
- 6b Wu B. Gao X. Yan Z. Huang W.-X. Zhou Y.-G. Tetrahedron Lett. 2015; 56: 4334
- 7a Barange DK. Raju BR. Kavala V. Kuo C.-W. Tu Y.-C. Yao C.-F. Tetrahedron 2010; 66: 3754
- 7b Han Y. Hou H. Yao R. Fu Q. Yan C.-G. Synthesis 2010; 4061
- 7c Rueping M. Parra A. Uria U. Besselièvre F. Merino E. Org. Lett. 2010; 12: 5680
- 7d Devi RB. Henrot M. De Paolis M. Maddaluno J. Org. Biomol. Chem. 2011; 9: 6509
- 7e Dong L. Deng L. Lim YH. Leung GY. C. Chen DY.-K. Chem. Eur. J. 2011; 17: 5778
- 7f Wu M.-Y. Wang M.-Q. Li K. Feng X.-W. He T. Wang N. Yu W.-Q. Tetrahedron Lett. 2011; 52: 679
- 7g Chawla R. Singh AK. Yadav LD. S. Tetrahedron Lett. 2012; 53: 3382
- 7h Jonek A. Berger S. Haak E. Chem. Eur. J. 2012; 18: 15504
- 7i Liu Z. Fan G.-P. Wang G.-W. Chem. Commun. 2012; 48: 11665
- 7j Kalpogiannaki D. Martini C.-I. Nikopoulou A. Nyxas JA. Pantazi V. Hadjiarapoglou LP. Tetrahedron 2013; 69: 1566
- 7k Xia L. Lee YR. Adv. Synth. Catal. 2013; 355: 1261
- 7l Yao C. Wang Y. Li T. Yu C. Li L. Wang C. Tetrahedron 2013; 69: 10593
- 7m Kasare S. Bankar SK. Ramasastry SS. V. Org. Lett. 2014; 16: 4284
- 7n Bosnidou A.-E. Kalpogiannaki D. Karanestora S. Nixas JA. Hadjiarapoglou LP. J. Org. Chem. 2015; 80: 1279
- 7o Riveira MJ. Quiroga GN. Mata EG. Gandon V. Mischne MP. J. Org. Chem. 2015; 80: 6515
- 7p Wang S. He L.-Y. Guo L.-N. Synthesis 2015; 47: 3191
- 7q Wei J. Nie B.-J. Peng R. Cheng X.-H. Wang S. He P. Synlett 2016; 27: 626
- 7r Kale A. Chennapuram M. Bingi C. Nanubolu JB. Atmakur K. Org. Biomol. Chem. 2016; 14: 582
- 7s Liu W. Lai X. Zha G. Xu Y. Sun P. Xia T. Shen Y. Org. Biomol. Chem. 2016; 14: 3603
- 8 Sinha D. Biswas A. Singh VK. Org. Lett. 2015; 17: 3302
- 9 Feng J. Lin L. Yu K. Liu X. Feng X. Adv. Synth. Catal. 2015; 357: 1305
- 10 Calter MA. Korotkov A. Org. Lett. 2015; 17: 1385
- 11 El-Sepelgy O. Haseloff S. Alamsetti SK. Schneider C. Angew. Chem. Int. Ed. 2014; 53: 7923
- 12 Kumar RK. Bi X. Chem. Commun. 2016; 52: 853
- 13a Zhang L. Fang G. Kumar RK. Bi X. Synthesis 2015; 47: 2317
- 13b Zi W. Toste D. Chem. Soc. Rev. 2016; 45 DOI: in press; 10.1039/c5cs00929d.
- 13c Yoshida H. ACS Catal. 2016; 6: 1799
- 14a Naodovic M. Yamamoto H. Chem. Rev. 2008; 108: 3132
- 14b Yamamoto Y. Chem. Rev. 2008; 108: 3199
- 14c Weibel J.-M. Blanc A. Pale P. Chem. Rev. 2008; 108: 3149
- 14d Álvarez-Corral M. Munoz-Dorado M. Rodríguez-García I. Chem. Rev. 2008; 108: 3174
- 14e Belmont P. Parker E. Eur. J. Org. Chem. 2009; 6075
- 14f Fang G. Bi X. Chem. Soc. Rev. 2015; 44: 8124
- 14g Sekine K. Yamada T. Chem. Soc. Rev. 2016; 45 DOI: in press; 10.1039/c5cs00895f.
- 15a Ding Q. Wu J. Org. Lett. 2007; 9: 4959
- 15b Shao Z. Zhang H. Chem. Soc. Rev. 2009; 38: 2745
- 15c Zhong C. Shi X. Eur. J. Org. Chem. 2010; 2999
- 15d Arróniz C. Gil-González A. Semak V. Escolano C. Bosch J. Amat M. Eur. J. Org. Chem. 2011; 3755
- 15e Loh CC. J. Enders D. Chem. Eur. J. 2012; 18: 10212
- 15f Du Z. Shao Z. Chem. Soc. Rev. 2013; 42: 1337
- 15g Deng Y. Kumar S. Wang H. Chem. Commun. 2014; 50: 4272
- 16a Hack D. Loh CC. J. Hartmann JM. Raabe G. Enders D. Chem. Eur. J. 2014; 20: 3917
- 16b Hack D. Chauhan P. Deckers K. Hermann GN. Mertens L. Raabe G. Enders D. Org. Lett. 2014; 16: 5188
- 16c Hack D. Chauhan P. Deckers K. Mizutani Y. Raabe G. Enders D. Chem. Commun. 2015; 51: 2266
- 16d Hack D. Dürr AB. Deckers K. Chauhan P. Seling N. Rübenach L. Mertens L. Raabe G. Schoenebeck F. Enders D. Angew. Chem. Int. Ed. 2016; 53: 1797
- 16e Kaya U. Chauchan P. Hack D. Deckers K. Puttreddy R. Rissanen K. Enders D. Chem. Commun. 2016; 52: 1669
- 17a Alemán J. Parra A. Jiang H. Jørgensen KA. Chem. Eur. J. 2011; 17: 6890
- 17b Storer RI. Aciro C. Jones LH. Chem. Soc. Rev. 2011; 40: 2330
- 17c Ni X. Li X. Wang Z. Cheng J.-P. Org. Lett. 2014; 16: 1786
- 17d Chauhan P. Mahajan S. Kaya U. Hack D. Enders D. Adv. Synth. Catal. 2015; 357: 253
- 18 CCDC 1474771 (5a) and CCDC 1474975 (5d) contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
- 19 Yang W. Du D.-M. Adv. Synth. Catal. 2011; 353: 1241
For examples of merging organo- and transition metal-catalysis, see:
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