Selenolactams as Synthetic Intermediates for the Synthesis of

Mar 1, 2018 - Actual reaction scales are indicated in respective data. ... (EI) m/z 189 (100, M+); HRMS (EI) calcd for C7H11NSe 189.0057, found 189.00...
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Cite This: J. Org. Chem. 2018, 83, 3078−3089

Selenolactams as Synthetic Intermediates for the Synthesis of Polycyclic Amines via Seleno-Claisen Rearrangements Fumitoshi Shibahara,* Masafumi Suzuki, Saki Kubota, Tomoki Fukunaga, Taro Udagawa, and Toshiaki Murai* Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193, Japan S Supporting Information *

ABSTRACT: A highly diastereoselective α-allylation of selenolactams with allyl halides is reported. DFT analyses and experimental observations suggested that this reaction proceeds via a Se-allylation of the eneselenolates of the lactams followed by a seleno-Claisen rearrangement. The thusobtained products could be efficiently transformed into polycyclic amines using a previously developed sequential addition of organometallic reagents and ring-closing metathesis.

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the reaction of a γ-selenolactam as a model substrate by density functional theory (DFT) calculations support the proposed pathway, i.e., a Se-allylation followed by a seleno-Claisen rearrangement, since the highest occupied molecular orbital (HOMO) of the selenolactam-derived eneselenolate is localized predominantly at the selenium atom (Figure 1, right).

INTRODUCTION Even though compounds that contain a selenocarbonyl group (CSe) often exhibit characteristic properties and reactivity,1 such compounds have scarcely been used as synthetic intermediates, which is probably due to their alleged instability and/or difficulties associated with their synthesis.2 Recently, we have developed a facile chalcogenation reaction of carbonyl compounds for the synthesis of such chalcogenocarbonyl compounds,3a and an investigation into the reactivity of these selenocarbonyl compounds shed light onto several aspects of their chemistry.3b−e Among those compounds, selenolactams4 represent a highly attractive structural motif, especially as synthetic precursors for cyclic amines, as the corresponding (oxo)lactams are widely used as synthetic intermediates for complex molecules. Therefore, we expected that the corresponding selenium isologues, given their particular reactivity, should allow other synthetically useful and unique transformations. Meanwhile, it has been reported that Claisen-type rearrangements of sulfur isologues of allyl enol ethers (thioClaisen rearrangements) proceed under considerably milder conditions than those of the corresponding oxo-Claisen rearrangement, which was ascribed to the relatively weak C−S bond.5 Considering the bonding behavior of the C−S bond, the selenium isologues should be more suitable substrates for the Claisen rearrangement, since the C−Se bond in the intermediate allyl eneselenol ethers should be weaker than that of the sulfur isologues. In fact, we have recently reported the highly diastereoselective α-allylation of chainlike selenoamides with allyl halides under mild conditions (0 °C to rt), which probably proceeds via a nucleophilic substitution of the allyl halides at the selenium atom on the corresponding eneselenolates, followed by a seleno-Claisen rearrangement.6 However, it remains unclear whether the reaction proceeds via the indicated sequence, given that the corresponding intermediates, i.e., the allyl eneselenol ethers, have not yet been detected.7 On the other hand, preliminary results of a theoretical examination of © 2018 American Chemical Society

Figure 1. HOMOs of cyclic Li-enolates calculated at the B3LYP/6311+G(d,p) level of theory.

Conversely, the HOMO of the corresponding enolate is located mostly at the carbon atom (Figure 1, left). Also, the energy barrier for the rearrangement process of the substrate, i.e., the allyl eneselenol ether of the γ-selenolactam, was calculated to be 2 kcal/mol, which would explain the experimentally observed high diastereoselectivity of these reactions. Further unsaturated bonds were introduced into the obtained allylated selenolactams using our previously reported methods.13 For example, the reaction of 8ba and an excess of allylmagnesium bromide in ether furnished the doubly allylated product 13a in good yield without any epimerization (Scheme 3). Sterically hindered 8bd reacted with allylmagnesium bromide to give 13b in good yield. The reaction could also be applied to 6- and 7-membered selenolactams, which furnished the corresponding products (13c,d) in high yield. Furthermore, a one-pot seleno-Claisen rearrangement followed by a double addition of allylmagnesium bromide proceeded successfully without a significant loss of efficiency at each step to give 13a in reasonable yield (Scheme 4). In addition, the sequential Scheme 4. One-Pot Reaction of Seleno-Claisen Rearrangement and Double Addition of Allylmagnesium Bromide

Figure 6. Example of energy diagram of the seleno-Claisen rearrangement leading to 8aa estimated by B3LYP/6-311++G(d,p) level of calculations.

should also be noted that the result also means that the reactions are synthetically complementary α-allylation methods, as the Scheme 3. Double Addition of Allylmagnesium Bromide

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DOI: 10.1021/acs.joc.8b00306 J. Org. Chem. 2018, 83, 3078−3089

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explorations of the synthetic importance of selenocarbonyl compounds are currently in progress in our laboratory.

addition of alkynyllithium and allylmagnesium bromide afforded adduct 14 with high diastereoselectivity (eq 3). In this case, the reaction efficiency was improved by treatment with methyl triflate prior to sequential addition of the organometallic reagents.13a

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EXPERIMENTAL SECTION

General Information. Chemical shifts of 1H and 13C are reported in ppm and are referenced to tetramethylsilane (δ = 0) and respective peaks of deuterated solvents as internal standards, respectively. 77Se chemical shifts are expressed in δ relative to the external standard Me2Se. All mass spectra (MS) and high-resolution mass spectra (HRMS) were obtained by ionizing samples via electron ionization (EI) in positive mode using a magnetic sector analyzer. Preparative recycling gel permeation chromatography (GPC) was carried out using CHCl3 as the eluent. Unless otherwise stated, compounds were obtained from common commercial suppliers and used as received. All reactions were carried out under argon atmosphere. Microwave irradiation syntheses in Scheme 5 were carried out with a Biotage Initiator in sealed test tube with external surface thermosensor at a temperature-maintained mode. General Procedure for Synthesis of Selenolactams 1, 5, and 7. To solutions of lactams (1.0 mmol), selenium (0.087 g, 1.1 mmol), and triethylamine (0.15 mL, 1.1 mmol) in toluene (5.0 mL) was added dichloromethylsilane (0.11 mL, 1.1 mmol) at rt, and the resulting suspensions were stirred at 115 °C for 3 h. The mixtures were cooled to rt, and saturated aqueous sodium bicarbonate was added. The separated aqueous layers were extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting oils were purified by column chromatography on silica gel (hexane/AcOEt) to give the corresponding selenolactams. Actual reaction scales are indicated in respective data. 1-Methylpyrrolidine-2-selenone22 (1a): 1.0 mmol scale, yellow liquid; yield 0.14 g (89%); 1H NMR (CDCl3) δ 1.90−2.04 (m, 2H), 2.93 (t, J = 8.8 Hz, 2H), 3.24 (s, 3H), 3.61 (t, J = 7.3 Hz, 2H). 1-Methylpiperidine-2-selenone23 (1b): 1.0 mmol scale, yellow liquid; yield 0.12 g (70%); 1H NMR (CDCl3) δ 1.70 (m, 2H), 1.95 (m, 2H), 3.03 (t, J = 6.3 Hz, 2H), 3.42 (t, J = 5.8 Hz, 2H), 3.58 (s, 3H). 1-Methylazepane-2-selenone22 (1c): 1.0 mmol scale, yellow liquid; yield 0.12 g (65%); 1H NMR (CDCl3) δ 1.67−1.78 (m, 6H), 3.27 (t, J = 5.8 Hz, 2H), 3.65 (s, 3H), 3.70 (t, J = 4.9 Hz, 2H). 1-Allylpyrrolidine-2-selenone (5a): 1.0 mmol scale, yellow liquid; yield 0.12 g, (62%); Rf = 0.13 (hexane/AcOEt = 5:1); IR (neat) 3078, 2916, 1683, 1642, 1516, 1464, 1415, 1307, 1267, 1219, 1181, 1086, 975, 931, 845, 735 cm−1; 1H NMR (CDCl3) δ 2.07 (quint, J = 7.6 Hz, 2H), 3.07 (t, J = 7.6 Hz, 2H), 3.64 (t, J = 7.6 Hz, 2H), 4.50 (d, J = 6.3 Hz, 2H), 5.29 (d, J = 17.0 Hz, 1H), 5.31 (d, J = 10.2 Hz, 1H), 5.84 (ddt, J = 17.0, 10.2, 6.3 Hz, 1H); 13C{1H} NMR (CDCl3) δ 20.0, 49.1, 53.3, 55.6, 119.7, 129.6, 203.3; 77Se NMR (CDCl3) δ 352.3; MS (EI) m/z 189 (100, M+); HRMS (EI) calcd for C7H11NSe 189.0057, found 189.0063. 1-Allylpiperidine-2-selenone (5b): 0.8 mmol scale, yellow liquid; yield 0.065 g (40%); Rf = 0.25 (hexane/AcOEt = 5:1); IR (neat) 2943, 1685, 1638, 1525, 1447, 1411, 1351, 1330, 1264, 1160, 1084, 1003, 932 cm−1; 1H NMR (CDCl3) δ 1.67 (quint, J = 6.3 Hz, 2H), 1.88 (quint, J = 6.3 Hz, 2H), 3.04 (t, J = 6.3 Hz, 2H), 3.30 (t, J = 6.3 Hz, 2H), 4.76 (d, J = 5.9 Hz, 2H), 5.24−5.31 (m, 2H), 5.91 (ddt, J = 17.1, 10.3, 5.9 Hz, 1H); 13C{1H} NMR (CDCl3) δ 20.1, 22.5, 45.3, 50.5, 61.2, 119.2, 140.2, 203.6; 77Se NMR (CDCl3) δ 509.3; MS (EI) m/z 203 (100, M+); HRMS (EI) calcd for C8H13NSe 203.0213, found 203.0214. 1-Allylazepane-2-selenone (5c): 1.0 mmol scale, yellow liquid; yield 0.090 g (43%); Rf = 0.28 (hexane/AcOEt = 5:1); IR (neat) 3076, 2928, 2854, 1685, 1640, 1512, 1448, 1340, 1238, 1185, 1115, 1067, 975, 951, 928 cm−1; 1H NMR (CDCl3) δ 1.64−1.76 (m, 6H), 3.29 (t, J = 5.9 Hz, 2H), 3.63 (t, J = 4.9 Hz, 2H), 4.80 (d, J = 5.4 Hz, 2H), 5.33−5.38 (m, 2H), 5.93 (ddt, J = 17.1, 10.3, 5.4 Hz, 1H); 13C{1H} NMR (CDCl3) δ 23.0, 25.6, 28.6, 50.4, 53.4, 63.0, 119.0, 130.0, 209.5; 77Se NMR (CDCl3) δ 597.5, 597.7; MS (EI) m/z 217 (100, M+); HRMS (EI) calcd for C9H15NSe 217.0370, found 217.0367. 1-Methyl-4-phenylpyrrolidine-2-selenone (7a): 5.0 mmol scale, yellow solid; yield 0.83 g (69%); mp 66.4−66.6 °C; Rf = 0.13 (hexane/ AcOEt = 5:1); IR (neat) 3082, 3051, 2952, 2926, 2862, 1601, 1535,

Finally, we attempted the ring-closing metathesis (RCM) of tetraallylated 13a (Scheme 5),20 which provided a chromatoScheme 5. Ring-Closing Metathesis of Multiallylated Cyclic Amines

graphically (GC, HPLC, SEC) inseparable mixture of two cyclized products that are distinguishable by NMR spectroscopy in excellent yield. The shape of the peaks in the 1H NMR spectrum of this mixture depended on temperature, which suggests that the mixture could potentially consist of diastereomers of 15a. Although the reasons of those observations are still unclear, we currently guess the product slowly underwent conformational isomerization on the nitrogen atom owing to the chromatographic behavior, but the possible generation of diastereomers that correspond to the newly formed bridge-head position of the three cycles and other stereo centers cannot be ruled out at this stage.21 Other ring-size amines, such as 13c and 13d, could also be cyclized to give 15c and 15d, respectively, in moderate yields in a similar manner.

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CONCLUSIONS In conclusion, we have demonstrated the utility of selenolactams as synthetic intermediates for the synthesis of polycyclic amines based on the characteristic reactivity of the selenocarbonyl moiety. The sequential allylation−seleno-Claisen rearrangement of such selenolactams proceeds smoothly even under cryogenic conditions, and the products are virtually obtained as a single diastereomer. These results clearly indicate a high potential for this strategy as a new route to polycyclic amines. It should be noted that selenolactams are generally easy to access and most can be handled under atmospheric conditions. Further 3083

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1460, 1390, 1300, 1075, 748, 697, 548 cm−1; 1H NMR (CDCl3) δ 3.15 (dd, J = 18.1, 6.8 Hz, 1H), 3.40 (s, 3H), 3.49 (dd, J = 18.1, 8.3 Hz, 1H), 3.63−3.73 (m, 2H), 4.07 (dd, J = 11.2, 7.8 Hz, 1H), 7.18−7.47 (m, 5H); 13C{1H} NMR (CDCl3) δ 38.3, 39.5, 56.4, 65.3, 126.5, 127.2, 128.8, 141.1, 202.3; 77Se NMR (CDCl3) δ 378.7; MS (EI) m/z 239 (100, M(79Se)+), 237 (48, M(77Se)+), 235 (19, M(75Se)+); HRMS (EI) calcd for C11H13NSe 239.0213, found 239.0211. 1-Allyl-4-phenylpyrrolidine-2-selenone (7b): 6.6 mmol scale, yellow solid; yield 1.1 g (65%), mp 38.8−40.7 °C; Rf = 0.30 (hexane/AcOEt = 5:1); IR (neat) 3454, 2967, 2926, 1682, 1604, 1520, 1450, 1399, 1300, 1294, 1233, 1075, 1028, 700, 625 cm−1; 1H NMR (CDCl3) δ 3.14 (dd, J = 17.9, 7.6 Hz, 1H), 3.49 (dd, J = 17.9, 8.9 Hz, 1H), 3.60−3.66 (m, 2H, NCH2), 3.99 (dd, J = 10.7, 5.3 Hz, 1H), 4.54 (d, J = 6.2 Hz, 2H), 5.29 (d, J = 11.2 Hz, 1H), 5.33 (d, J = 16.0 Hz, 1H), 5.85 (ddt, J = 16.0, 11.2, 6.2 Hz, 1H), 7.17−7.36 (m, 5H); 13C{1H} NMR (CDCl3) δ 39.9, 53.7, 56.9, 62.7, 120.5, 126.9, 127.6, 129.3, 141.5, 129.9, 203.2; 77Se NMR (CDCl3) δ 378.9; MS (EI) m/z 265 (95, M(79Se)+), 263 (48, M(77Se)+), 261 (19, M(75Se)+); HRMS (EI) calcd for C13H15NSe 265.0370, found 265.0367. 3-Benzyl-1-methyl-4-phenylpyrrolidine-2-selenone (7c). A cis/ trans mixture of 3-benzyl-1-methyl-4-phenylpyrrolidin-2-one was used: 1.8 mmol scale, yellow solid; yield 0.082 g (74%), mp 95.8− 96.2 °C; Rf = 0.31 (hexane/AcOEt = 5:1); IR (neat) 3059, 3027, 3002, 2948, 2924, 2866, 1540, 1493, 1454, 1390, 1291, 1252, 1101, 1052, 755, 697 cm−1; 1H NMR (CDCl3) δ 3.17−3.28 (m, 2H), 3.35 (s, 3H), 3.37−3.41 (m, 2H), 3.45 (dd, J = 12.2, 5.4 Hz, 1H), 3.61 (dd, J = 12.2, 8.8 Hz, 1H), 6.94−7.48 (m, 10H); 13C{1H} NMR (CDCl3) δ 38.4, 39.3, 49.4, 64.7, 67.0, 126.6, 126.8, 127.1, 128.3, 128.9, 129.5, 137.9, 142.1, 206.8; 77Se NMR (CDCl3) δ 375.3; MS (EI) m/z 330 (44, M(80Se)+), 329 (100, M(79Se)+), 327 (100, M(78Se)+), 238 (14, M+ − C7H7); HRMS (EI) calcd for C18H19NSe 329.0683, found 329.0681. 1,5-Dimethylpyrrolidine-2-selenone (7d): 1.0 mmol scale, yellow liquid; yield 0.099 g (73%); Rf = 0.45 (hexane/AcOEt = 1:1); IR (neat) 3454, 2967, 2926, 1682, 1604, 1520, 1450, 1399, 1300, 1294, 1233, 1075, 1028, 700, 625 cm−1; 1H NMR (CDCl3) δ 1.35 (d, J = 6.3 Hz, 3H), 1.66−1.74 (m, 1H), 2.22−2.34 (m, 1H), 2.91−3.12 (m, 2H), 3.31 (s, 3H), 3.92 (ddq, J = 13.0, 6.3 Hz, 1H); 13C{1H} NMR (CDCl3) δ 18.8, 28.4, 36.0, 47.3, 65.5, 202.4; 77Se NMR (CDCl3) δ 362.1; MS (EI) 177 (63, M(79Se)+), 175 (30, M(78Se)+); HRMS (EI) calcd for C6H11NSe 177.0057, found 177.0060. Typical Procedure for Allylation−Seleno-Claisen Rearrangement of Selenolactams. To THF solutions (1.0 mL) of LDA, generated from i-Pr2NH (0.070 mL, 0.50 mmol) and n-BuLi (1.6 M hexane solution, 0.31 mL, 0.50 mmol), were added selenolactams (0.50 mmol) at 0 °C, and the mixtures were stirred for 10 min at that temperature. Allyl bromide (0.035 mL, 0.41 mmol) was then added to the resulting solutions, and the mixtures were stirred for 10 min at 0 °C. The mixtures were poured onto brine and extracted with Et2O. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residues were purified by column chromatography on silica gel to give the corresponding 3-allylselenolactams. Actual reaction scales are indicated in the respective data. 3-Allyl-1-methylpyrrolidine-2-selenone (2a): 6.7 mmol scale, yellow liquid; yield 1.2 g (87%); Rf = 0.12 (hexane/AcOEt = 5:1); IR (neat) 3073, 2927, 2874, 1843, 1684, 1639, 1536, 1467, 1449, 1399, 1305, 1250, 1088, 1024, 997, 916 cm−1; 1H NMR (CDCl3) δ 1.78−1.87 (m, 1H), 2.20−2.36 (m, 2H), 2.90−2.99 (m, 2H), 3.36 (s, 3H), 3.53− 3.67 (m, 2H), 5.06 (d, J = 10.3 Hz, 1H), 5.13 (d, J = 17.1 Hz, 1H), 5.78 (ddt, J = 17.1, 10.3, 6.8 Hz, 1H); 13C{1H} NMR (CDCl3) δ 27.6, 38.3, 45.2, 57.0, 61.2, 118.8, 133.7, 210.7; 77Se NMR (CDCl3) δ 344.3; MS (EI) m/z 203 (100, M(79Se)+), 201 (54, M(77Se)+), 199 (25, M(75Se)+); HRMS (EI) calcd for C8H13NSe 203.0213, found 203.0215. 3-Allyl-1-methylpiperidine-2-selenone (2b): 0.6 mmol scale, pale yellow liquid; yield 0.10 g (66%); Rf = 0.25 (hexane/AcOEt = 5:1); IR (neat) 3072, 2943, 2864, 1734, 1638, 1536, 1450, 1400, 1353, 1333, 1215, 1097, 1002, 915, 729, 643 cm−1; 1H NMR (CDCl3) δ 1.65−1.73 (m, 1H), 1.74−1.90 (m, 2H), 1.93−2.04 (m, 1H), 3.01 (ddt, J = 13.7, 10.3, 8.8 Hz, 1H), 3.14 (ddd, J = 8.8, 5.9, 3.4 Hz, 1H), 3.40 (ddd, J = 8.8, 5.9, 3.4 Hz, 1H), 3.33−3.48 (m, 2H), 3.57 (s, 3H), 5.08 (d, J = 10.3 Hz, 1H), 5.11 (d, J = 8.9 Hz, 1H), 5.77−5.82 (m, 1H); 13C{1H} NMR

(CDCl3) δ 19.3, 23.0, 40.8, 48.4, 50.9, 54.3, 117.2, 136.2, 208.1; 77Se NMR (CDCl3) δ 519.8; MS (EI) m/z 217 (100, M(79Se)+), 215 (56, M(77Se)+), 213 (29, M(75Se)+), 176 (6, M+ − C3H5); HRMS (EI) calcd for C9H15NSe 217.0370, found 217.0363. 3-Allyl-1-methylazepane-2-selenone (2c): 0.54 mmol scale, yellow liquid; yield 0.094 g (63%); Rf = 0.30 (hexane/AcOEt = 5:1); IR (neat) 3071, 2927, 2855, 1638, 1508, 1451, 1394, 1333, 1290, 1249, 1098, 1065, 998, 914, 889 cm−1; 1H NMR (CDCl3) δ 1.22−1.30 (m, 1H), 1.50−1.78 (m, 5H), 2.30 (ddt, J = 14.1, 9.7, 3.9 Hz, 1H), 2.88 (dd, J = 5.4, 3.9 Hz, 2H), 3.60−3.65 (m, 1H), 3.64 (s, 3H), 4.00 (dd, J = 13.2, 11.2 Hz, 1H), 5.01 (d, J = 11.2 Hz, 1H), 5.02 (d, J = 18.5 Hz, 1H), 5.80 (ddt, J = 18.5, 11.2, 3.9 Hz, 1H); 13C{1H} NMR (CDCl3) δ 24.2, 26.9, 28.4, 42.1, 49.3, 51.5, 55.1, 116.5, 136.8, 213.7; 77Se NMR (CDCl3) δ 553.3−541.8 (broad); MS (EI) m/z 231 (100, M+); HRMS (EI) calcd for C10H17NSe 231.0526, found 231.0523. 1,3-Diallylpyrrolidine-2-selenone (6a): 0.41 mmol scale, pale yellow liquid; yield 0.043 g (46%); Rf = 0.25 (hexane/AcOEt = 5:1); IR (neat) 3075, 2974, 2923, 2875, 1684, 1640, 1510, 1465, 1449, 1414, 1309, 1265, 1216, 1189, 1128, 1093, 1025, 994, 918 cm−1; 1H NMR (CDCl3) δ 1.76−1.85 (m, 1H), 2.19−2.38 (m, 2H), 2.91−3.01 (m, 2H), 3.47− 3.61 (m, 2H), 4.45 (dd, J = 14.8, 6.3 Hz, 1H), 4.57 (dd, J = 14.8, 6.3 Hz, 1H), 5.09 (d, J = 10.3 Hz, 1H), 5.12 (d, J = 17.0 Hz, 1H), 5.29 (d, J = 17.0 Hz, 1H), 5.30 (d, J = 11.2 Hz, 1H), 5.74−5.89 (m, 2H); 13C{1H} NMR (CDCl3) δ 25.5, 38.8, 53.5, 54.3, 57.1, 117.4, 119.6, 129.6, 134.9, 207.6; 77Se NMR (CDCl3) δ 347.2; MS (EI) m/z 229 (100, M+); HRMS (EI) calcd for C10H15NSe 229.0370, found 229.0362. 1,3-Diallylpiperidine-2-selenone (6b): 0.41 mmol scale, yellow liquid; yield 0.074 g (76%); Rf = 0.37 (hexane/AcOEt = 5:1); IR (neat) 3074, 2945, 2865, 1639, 1516, 1411, 1384, 1353, 1335, 1262, 1165, 1126, 999, 918 cm−1; 1H NMR (CDCl3) δ 1.64−1.98 (m, 4H), 2.40 (ddt, J = 13.7, 9.3, 4.4 Hz, 1H), 3.01−3.14 (m, 2H), 3.27−3.39 (m, 2H), 4.68 (dd, J = 14.3, 5.9 Hz, 1H), 4.90 (dd, J = 14.3, 5.9 Hz, 1H), 5.09 (d, J = 8.9 Hz, 1H), 5.09 (d, J = 17.1 Hz, 1H), 5.25 (d, J = 18.5 Hz, 1H), 5.28 (d, J = 10.3 Hz, 1H), 5.80 (ddt, J = 18.5, 10.3, 5.9 Hz, 1H), 5.92 (ddt, J = 17.1, 8.9, 5.9 Hz, 1H); 13C{1H} NMR (CDCl3) δ 19.2, 23.0, 40.8, 50.9, 50.9, 61.8, 117.1, 118.9, 130.1, 135.9, 208.8; 77Se NMR (CDCl3) δ 509.9; MS (EI) m/z 243 (100, M+); HRMS (EI) calcd for C11H17NSe 243.0526, found 243.0524. 1,3-Diallylazepane-2-selenone (6c): 0.41 mmol scale, yellow liquid; yield 0.07 g (66%); Rf = 0.50 (hexane/AcOEt = 5:1); IR (neat) 3073, 2930, 2855, 1639, 1496, 1447, 1410, 1340, 1227, 1195, 1122, 997, 915, 809 cm−1; 1H NMR (CDCl3) δ 1.32−1.86 (m, 6H), 2.40 (dt, J = 14.0, 9.0 Hz, 1H), 2.90−2.95 (m, 2H), 3.60 (ddd, J = 14.3, 5.8, 3.1 Hz, 1H), 3.82 (ddd, J = 14.3, 10.3, 2.2 Hz, 1H), 4.74 (dd, J = 14.4, 6.3 Hz, 1H), 5.04−5.13 (m, 3H), 5.30 (dd, J = 8.5, 1.4 Hz, 2H), 5.82−5.99 (m, 2H); 13 C{1H} NMR (CDCl3) δ 24.9, 27.0, 28.5, 42.2, 52.2, 52.3, 63.1, 116.8, 119.1, 130.8, 136.9, 215.1; 77Se NMR (CDCl3) 498.5−513.9 (br); MS (EI) m/z 257 (100, M+); HRMS (EI) calcd for C12H19NSe 257.0683, found 257.0683. 3-Allyl-1-methyl-4-phenylpyrrolidine-2-selenone (8aa): 0.41 mmol scale, yellow solid; yield 0.088 g (76%); Rf = 0.45 (hexane/ AcOEt = 5:1); mp 55.4−57.3 °C; IR (neat) 3067, 3027, 3001, 2975, 2923, 2869, 1685, 1638, 1601, 1540, 1455, 1396, 1294, 1097, 995, 915, 754, 700 cm−1; 1H NMR (CDCl3) δ 2.72 (t, J = 5.9 Hz, 2H), 3.07 (dt, J = 11.7, 5.9 Hz, 1H), 3.35−3.47 (m, 1H), 3.40 (s, 3H), 3.60 (dd, J = 11.7, 6.8 Hz, 1H), 3.97 (dd, J = 11.7, 9.3 Hz, 1H), 5.07 (d, J = 17.1 Hz, 1H), 5.07 (d, J = 10.3 Hz, 1H), 5.74 (ddt, J = 17.1, 10.3, 5.9 Hz, 1H), 7.17−7.35 (m, 5H); 13C{1H} NMR (CDCl3) δ 37.4, 38.5, 44.1, 64.5, 64.7, 118.1, 127.3, 127.4, 129.1, 141.3, 134.5, 206.4; 77Se NMR (CDCl3) δ 369.7; MS (EI) m/z 279 (100, M(79Se)+), 277 (49, M(77Se)+), 275 (19, M(75Se)+), 173 (32, M+ − C2H2Se); HRMS (EI) calcd for C14H17NSe 279.0526, found 279.0529. 1-Methyl-4-phenyl-3-(1-phenylallyl)pyrrolidine-2-selenone (8ab): 0.41 mmol scale, pale yellow liquid; yield 0.10 g (73%); Rf = 0.50 (hexane/AcOEt = 5:1); IR (neat) 3081, 3059, 3027, 3002, 2929, 2875, 1637, 1601, 1539, 2493, 1452, 1400, 1307, 1245, 1090, 1032, 1001, 921, 761, 702 cm−1; 1H NMR (CDCl3) δ 2.55 (dd, J = 11.7, 7.8 Hz, 1H), 3.12 (dd, J = 11.7, 2.2 Hz, 1H), 3.14 (s, 3H), 3.33 (dt, J = 7.8, 2.2 Hz, 1H), 3.69 (dd, J = 7.8, 5.8 Hz, 1H), 4.61 (dd, J = 5.9, 2.4 Hz, 1H), 5.04 (dd, J = 15.6 Hz, 1H), 5.22 (d, J = 9.7 Hz, 1H), 6.17 (ddd, J = 15.6, 9.7, 3084

DOI: 10.1021/acs.joc.8b00306 J. Org. Chem. 2018, 83, 3078−3089

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5.8 Hz, 1H), 7.09−7.43 (m, 10H); 13C{1H} NMR (CDCl3) δ 38.2, 41.4, 50.7, 65.8, 70.4, 116.1, 126.6, 127.3, 127.5, 128.2, 128.7, 129.3, 138.1, 139.3, 144.3, 206.1; 77Se NMR (CDCl3) δ 384.4; MS (EI) m/z 355 (100, M(79Se)+), 353 (71, M(77Se)+), 351 (26, M(75Se)+), 117 (97, M+-C11H12NSe); HRMS (EI) calcd for C20H21NSe 355.0839, found 355.0843. 3-(But-3-en-2-yl)-1-methyl-4-phenylpyrrolidine-2-selenone (8ac): 0.41 mmol scale, pale yellow liquid; yield 0.060 g, (50%), dr = 83:17, Rf = 0.37 (hexane/AcOEt = 5:1); IR (neat) 3080, 3062, 3026, 2999, 2962, 2930, 2875, 1637, 1602, 1536, 1455, 1400, 1306, 1253, 1086, 998, 916, 758, 701 cm−1; 1H NMR (CDCl3) δ 1.00 (d, J = 6.8 Hz, 2.5H), 1.06 (d, J = 7.3 Hz, 0.5H), 3.24−3.38 (m, 3H, PhCH), 3.39 (s, 0.5H), 3.43 (s, 2.5H), 3.59 (dd, J = 12.2, 4.4 Hz, 1H), 3.97 (dd, J = 12.2, 8.8 Hz, 1H), 5.02 (d, J = 10.2 Hz, 0.8H), 5.07 (d, J = 17.1 Hz, 0.8H), 5.14 (d, J = 10.7 Hz, 0.2H), 5.17 (dd, J = 16.1 Hz, 0.2H), 5.54−5.57 (m, 1H), 7.09−7.32 (m, 5H); 13C{1H} NMR (CDCl3) δ 12.3, 16.7, 38.3, 38.4, 40.1, 40.2, 40.57, 40.65, 66.2, 66.3, 70.9, 71.6, 114.5, 116.4, 126.79, 126.82, 127.1, 127.2, 129.09, 129.16, 138.1, 141.2, 144.10, 144.12, 206.1, 206.4; 77Se NMR (CDCl3) δ 368.4, 368.5; MS (EI) m/z 293 (80, M(79Se)+), 291 (34, M(77Se)+), 389 (15, M(75Se)+), 117 (97, M+-C11H12NSe); HRMS (EI) calcd for C15H19NSe 293.0683, found 293.0681. 1-Methyl-3-(2-methylbut-3-en-2-yl)-4-phenylpyrrolidine-2-selenone (8ad): 0.41 mmol scale, pale yellow liquid; yield 0.060 g (48%); Rf = 0.50 (hexane/AcOEt = 5:1); IR (neat) 3080, 3060, 3026, 2963, 2926, 2875, 1636, 1603, 1529, 1460, 1399, 1365, 1307, 1170, 1089, 1046, 916, 768, 750, 700 cm−1; 1H NMR (CDCl3) δ 1.26 (s, 3H), 1.41 (s, 3H), 3.09 (brd, 1H), 3.40 (s, 3H), 3.40−3.44 (m, 2H), 4.01 (dd, J = 12.2, 8.3 Hz, 1H), 5.00 (d, J = 17.6 Hz, 1H), 5.02 (d, J = 10.3 Hz, 1H), 5.85 (dd, J = 17.6, 10.3, Hz, 1H), 7.05−7.31 (m, 5H); 13C{1H} NMR (CDCl3) δ 23.4, 27.5, 38.9, 41.6, 42.7, 65.6, 75.5, 112.2, 129.1, 126.1, 126.9, 145.3, 145.9, 203.7; 77Se NMR (CDCl3) δ 484.0; MS (EI) m/z 307 (100, M(79Se)+), 305 (22, M(77Se)+), 303 (8, M(75Se)+), 238 (65, M+ − C5H9); HRMS (EI) calcd for C16H21NSe 307.0839, found 307.0839. 1,3-Diallyl-4-phenylpyrrolidine-2-selenone (8ba): 0.48 mmol scale, pale yellow liquid; yield 0.068 g (56%); Rf = 0.50 (hexane/AcOEt = 5:1); IR (neat) 3075, 3027, 2977, 2923, 1640, 1603, 1508, 1459, 1414, 1308, 1259, 1119, 1081, 995, 919, 757, 700 cm−1; 1H NMR (CDCl3) δ 2.72 (brt, 2H), 3.09 (dt, J = 12.2, 6.3 Hz, 1H), 3.36 (ddd, J = 12.2, 8.2, 6.8 Hz, 1H), 3.54 (dd, J = 11.7, 6.8 Hz, 1H), 3.92 (dd, J = 11.7, 8.2 Hz, 1H), 4.51 (dd, J = 14.6, 6.3 Hz, 1 H), 4.60 (dd, J = 14.6, 6.3 Hz, 1H), 5.08 (d, J = 10.2 Hz, 1H), 5.12 (d, J = 17.0 Hz, 1H), 5.29 (d, J = 10.2 Hz, 1H), 5.32 (d, J = 17.2 Hz, 1H), 5.75 (ddt, J = 17.0, 10.2, 6.8 Hz, 1H), 5.88 (ddt, J = 17.2, 10.2, 6.3 Hz, 1H), 7.16−7.35 (m, 5H); 13 C{1H} NMR (CDCl3) δ 37.3, 43.8, 53.6, 61.7, 64.9, 118.1, 120.0, 127.1, 127.3, 128.9, 129.6, 134.4, 141.3, 206.8; 77Se NMR (CDCl3) δ 382.3; MS (EI) m/z 305 (53, M(79Se)+), 303 (27, M(77Se)+), 264 (16, M+ − C3H5); HRMS (EI) calcd for C16H19NSe 305.0683, found 305.0681. 1-Allyl-4-phenyl-3-(1-phenylallyl)pyrrolidine-2-selenone (8bb): 0.41 mmol scale, pale yellow liquid; yield 0.11 g (75%); Rf = 0.50 (hexane/AcOEt = 5:1); IR (neat) 3080, 3060, 3026, 2928, 2876, 1639, 1600, 1513, 1493, 1452, 1415, 1312, 1267, 1076, 994, 922, 761, 706 cm−1; 1H NMR (CDCl3) δ 2.61 (dd, J = 11.7, 8.3 Hz, 1H), 3.10 (dd, J = 11.7, 2.0 Hz, 1H), 3.37 (dt, J = 8.3, 2.0 Hz, 1H), 3.70 (brd, 1H), 4.33 (d, J = 6.8 Hz, 2H), 4.62 (d, J = 5.4 Hz, 1H), 5.03 (d, J = 17.6 Hz, 1H), 5.09 (d, J = 17.1 Hz, 1H), 5.13 (d, J = 11.2 Hz, 1H), 5.21 (d, J = 10.7 Hz, 1H), 5.55 (ddt, J = 17.6, 11.2, 6.8 Hz, 1H), 6.17 (ddd, J = 17.1, 10.7, 5.4 Hz, 1H), 7.09−7.43 (m, 10H); 13C{1H} NMR (CDCl3) δ 41.1, 50.8, 53.8, 63.1, 70.8, 118.1, 120.5, 126.6, 127.3, 127.5, 128.3, 128.9, 129.3, 129.4, 138.3, 139.2, 144.5, 206.2; 77Se NMR (CDCl3) δ 379.7; MS (EI) m/z 381 (100, M(79Se)+), 379 (55, M(77Se)+), 377 (23, M(75Se)+), 264 (50, M+ − C9H9); HRMS (EI) calcd for C22H23NSe 381.0996, found 381.0996. 1-Allyl-3-(2-methylbut-3-en-2-yl)-4-phenylpyrrolidine-2-selenone (8bd): 0.31 mmol scale, pale yellow liquid; yield 0.059 g (44%); Rf = 0.62 (hexane/AcOEt = 5:1); IR (neat) 3081, 3026, 2964, 2924, 2875, 1639, 1603, 1506, 1458, 1413, 1315, 1257, 1171, 919, 754, 700 cm−1; 1 H NMR (CDCl3) δ 1.25 (s, 3H), 1.41 (s, 3H), 3.11 (brd, 1H), 3.40 (m, 2H), 3.91 (dd, J = 11.7, 8.2 Hz, 1H), 4.48 (dd, J = 14.1, 6.8 Hz,

1H), 4.71 (dd, J = 14.1, 6.3 Hz, 1H), 5.07 (d, J = 11.2 Hz, 1H), 5.08 (d, J = 17.0 Hz, 1H), 5.31 (d, J = 10.2 Hz, 1H), 5.35 (d, J = 16.1 Hz, 1H), 5.82−5.95 (m, 2H), 7.05−7.31 (m, 5H); 13C{1H} NMR (CDCl3) δ 23.3, 27.6, 41.6, 42.3, 53.9, 62.7, 75.6, 112.2, 120.5, 126.2, 126.9, 129.1, 129.7, 145.4, 146.0, 204.0; 77Se NMR (CDCl3) δ 479.7; MS (EI) m/z 333 (100, M+); HRMS (EI) calcd for C18H23NSe 333.0996, found 333.0995. 3-Benzyl-1-methyl-4-phenyl-3-(1-phenylallyl)pyrrolidine-2-selenone (8cb): 0.41 mmol scale, pale yellow powder; yield 0.087 g (48%); mp 119−125 °C dec; Rf = 0.50 (hexane/AcOEt = 5:1); IR (neat) 3060, 3028, 3003, 2928, 2883, 1735, 1684, 1602, 1538, 1496, 1454, 1398, 1306, 1249, 1075, 1002, 926, 749, 699 cm−1; 1H NMR (CDCl3) δ 2.85 (d, J = 15.1 Hz, 1H), 2.97 (dd, J = 11.7, 9.3 Hz, 1H), 3.10 (dd, J = 11.7, 6.8 Hz, 1H), 3.22 (s, 3H), 3.45 (d, J = 15.1 Hz, 1H), 3.94 (dd, J = 9.3, 6.8 Hz, 1H), 4.70 (d, J = 9.8 Hz, 1H), 5.33 (d, J = 15.6 Hz, 1H), 5.37 (d, J = 10.3 Hz, 1H), 6.63 (ddd, J = 15.6, 10.3, 9.8 Hz, 1H), 6.87−7.32 (m, 13H), 7.75 (d, J = 6.8 Hz, 2H); 13C{1H} NMR (CDCl3) δ 38.9, 42.5, 43.8, 58.4, 62.7, 70.3, 119.4, 125.8, 126.9, 127.1, 127.3, 128.0, 128.1, 128.9, 129.8, 130.5, 136.8, 138.0, 138.5, 140.5, 210.4; 77Se NMR (CDCl3) δ 408.6; MS (EI) m/z 445 (54, M(79Se)+), 443 (28, M(77Se)+), 441 (10, M(75Se)+), 354 (100, M+ − C7H7), 328 (21, C9H9), 237 (7, M+ − C16H16), 117 (78, M− -C18H18NSe); HRMS (EI) calcd for C27H27NSe 445.1309, found 445.1310. 3-Benzyl-3-(but-3-en-2-yl)-1-methyl-4-phenylpyrrolidine-2-selenone (8cc): 0.25 mmol scale, pale yellow liquid; yield 0.038 g (40%); Rf = 0.45 (hexane/AcOEt = 5:1); IR (neat) 3060, 3028, 2931, 1531, 1496, 1453, 1295, 1271, 1254, 1099, 1033, 917, 753, 735, 701 cm−1; 1H NMR (CDCl3) δ 1.29 (d, J = 6.8 Hz, 3H), 2.91 (d, J = 17.6 Hz, 1H), 3.12 (d, J = 17.6 Hz, 1H), 3.22 (dd, J = 9.3, 7.8 Hz, 1H), 3.28 (dd, J = 6.8, 7.8 Hz, 1H), 3.40 (s, 3H), 3.74 (dd, J = 8.8, 6.8 Hz, 1H), 3,75 (dd, J = 9.3, 6.8 Hz, 1H), 5.12 (d, J = 10.3 Hz, 1H), 5.23 (d, J = 17.1 Hz, 1H), 5.99 (ddd, J = 17.1, 10.3, 8.8 Hz, 1H), 6.92−7.26 (m, 10H); 13C{1H} NMR (CDCl3) δ 17.0, 38.8, 41.1, 45.3, 47.4, 62.4, 67.9, 117.0, 126.3, 127.3, 127.5, 128.2, 129.5, 130.6, 137.6, 138.0, 140.0, 210.7; 77Se NMR (CDCl3) δ 408.6; MS (EI) m/z 383 (81, M(79Se)+), 381 (41, M(77Se)+), 379 (15, M(75Se)+), 328 (32, M+ − C4H7), 292 (100, M+ − C7H7), 91 (51, M+ − C15H18NSe); HRMS (EI) calcd for C22H25NSe 383.1152, found 383.1154. 3-Benzyl-1-methyl-3-(2-methylbut-3-en-2-yl)-4-phenylpyrrolidine-2-selenone (8cd): 0.25 mmol scale, pale yellow liquid; yield 0.036 g (30%); Rf = 0.35 (hexane/AcOEt = 5:1); IR (neat) 3058, 3028, 2956, 2922, 1601, 1534, 1495, 1466, 1452, 1321, 1253, 1104, 1075, 916, 750, 696 cm−1; 1H NMR (CDCl3) δ 1.31 (s, 3H), 1.50 (s, 3H), 2.90 (d, J = 15.3 Hz, 1H), 3.52 (s, 3H), 3.68 (dd, J = 12.1, 3.6 Hz, 1H), 3.86−3.98 (m, 3H), 5.16 (d, J = 17.5 Hz, 1H), 5.21 (d, J = 10.8 Hz, 1H), 6.30 (dd, J = 17.5, 10.8 Hz, 1H), 6.77−6.98 (m, 10H); 13C{1H} NMR (CDCl3) δ 22.9, 24.5, 39.2, 39.3, 44.2, 46.2, 64.6, 71.8, 113.3, 125.1, 126.3, 127.5, 127.8, 128.8, 129.7, 139.2, 140.5, 146.0, 208.7; 77Se NMR (CDCl3) δ 463.2; MS (EI) m/z 397 (100, M(79Se)+), 395 (49, M(77Se)+), 328 (17, M − C5H9); HRMS (EI) calcd for C23H27NSe 397.1309, found 397.1305. 3-Allyl-1,5-dimethylpyrrolidine-2-selenone (8da): 0.50 mmol scale, pale yellow liquid; yield 0.056 g (52%); dr = 50:50; Rf = 0.30 (hexane/ AcOEt = 5:1); IR (neat) 3073, 2969, 2927, 1684, 1639, 1515, 1446, 1398, 1379, 1294, 1236, 1126, 1076, 916, 639 cm−1; 1H NMR (CDCl3) δ 1.30 (d, J = 6.3 Hz, 1.5H), 1.37 (d, J = 6.3 Hz, 1.5H), 1.87 (dd, J = 13.2, 8.8 Hz, 0.5H), 2.02 (dd, J = 13.2, 7.8 Hz, 0.5H), 2.29 (ddt, J = 8.8, 7.7, 7.3 Hz, 1H), 2.44 (m, 0.5H), 2.82 (m, 0.5H), 2.92−3.09 (m, 2H), 3.30 (s, 1.5H), 3.32 (s, 1.5H), 3.76 (tq, J = 13.2, 6.3 Hz, 0.5H), 3.86 (tq, J = 13.2, 6.3 Hz, 0.5H), 5.07 (d, J = 10.2 Hz, 1H), 5.11 (d, J = 18.0 Hz, 1H), 5.78 (ddt, J = 18.0, 10.2, 7.3 Hz, 1H); 13C{1H} NMR (CDCl3) δ 18.5, 19.8, 35.6, 34.1, 36.1, 36.3, 38.9, 39.5, 54.9, 55.3, 63.7, 63.9, 117.0, 117.2, 135.0, 135.3, 206.5, 207.2; 77Se NMR (CDCl3) 355.3, 355.8; MS (EI) m/z 217 (94, M(79Se)+), 216 (43, M(78Se)+); HRMS (EI) calcd for C9H15NSe 217.0370, found 217.0375. 1,5-dimethyl-3-(1-phenylallyl)pyrrolidine-2-selenone (8db): 0.5 mmol, yellow solid; yield 0.051 g (35%); dr = 71:29; mp 62.3−66.7 °C; Rf = 0.40 (hexane/AcOEt = 5:1); IR (neat) 3073, 3059, 3027, 2975, 2935, 2895, 2870, 1636, 1527, 1451, 1400, 1282, 1247, 1126, 1068, 924 cm−1; 1H NMR (CDCl3) δ 0.47 (d, J = 6.8 Hz, 0.75H), 1.10 (d, J = 6.3 3085

DOI: 10.1021/acs.joc.8b00306 J. Org. Chem. 2018, 83, 3078−3089

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Hz, 2.25H), 1.49 (dt, J = 11.7, 5.8 Hz, 0.25H), 1.69−1.76 (m, 0.75H), 2.22 (dd, J = 13.1, 7.3 Hz, 0.75H), 2.23 (dd, J = 13.1, 2.4 Hz, 0.25H), 2.38 (m, 1H), 3.04 (s, 2.25H), 3.18 (s, 0.75H), 3.57−3.66 (m, 1H), 4.54 (brdd, 0.75H), 4.86 (brd, 0.25H), 5.18 (d, J = 17.1 Hz, 0.25H), 5.19 (d, J = 17.6 Hz, 0.75H), 5.24−5.27 (m, 0.25H), 5.28 (d, J = 10.7 Hz, 0.75H), 6.14−6.22 (m, 1H), 7.19−7.39 (m, 5H); 13C{1H} NMR (CDCl3) δ 18.6, 19.5, 28.6, 31.1, 35.7, 36.5, 38.9, 39.5, 50.1, 50.3, 60.4, 60.5, 63.9, 64.9, 115.0, 115.4, 127.0, 127.3, 127.9, 128.0, 128.5, 128.7, 129.5, 138.8, 139.3, 139.4, 206.2, 206.4; 77Se NMR (CDCl3) δ 366.4, 375.1; MS (EI) m/z 293 (100, M(79Se)+), 291 (63, M(77Se)+), 117 (89, M+ − C6H10NSe); HRMS (EI) calcd for C15H19NSe 293.0683, found 293.0682. 1,5-Dimethyl-3-(2-methylbut-3-en-2-yl)pyrrolidine-2-selenone (8dd): 0.5 mmol scale; pale yellow liquid; yield 0.045 g (39%); dr = 67:33; Rf = 0.40 (hexane/AcOEt = 5:1); IR (neat) 3079, 2925, 2870, 1686, 1636, 1501, 1291, 1240, 1172, 1122, 1065, 1022, 914 cm−1; 1H NMR (CDCl3) δ 1.26−1.39 (m, 9H), 1.72 (ddd, J = 13.2, 9.3, 6.8 Hz, 1H), 2.21 (ddd, J = 12.7, 7.8, 4.9 Hz, 0.7H), 2.27−2.35 (m, 0.3H), 2.80 (t, J = 6.8 Hz, 0.3H), 2.99 (t, J = 6.8 Hz, 0.7H), 3.27 (s, 2H), 3.28 (s, 1H), 3.56 (sext, J = 13.6, 6.8 Hz, 0.3H), 3.78 (sext, J = 13.6, 6.8 Hz, 0.7H), 4.96−5.02 (m, 2H), 5.91 (dd, J = 17.1, 10.7 Hz, 0.7H), 6.08 (dd, J = 17.1, 10.7 Hz, 0.3H); 13C{1H} NMR (CDCl3) δ 19.5, 19.8, 24.1, 24.8, 26.3, 26.9, 32.2, 32.8, 36.4, 36.5, 39.9, 40.6, 62.5, 63.5, 64.0, 64.3, 111.7, 111.8, 145.9, 146.0, 204.0, 204.7; 77Se NMR (CDCl3) δ 448.8, 461.8; MS (EI) m/z 245 (68, M(79Se)+), 243 (34, M(77Se)+), 175 (48, M+ − C5H9), 69 (20, M+ − C6H10NSe); HRMS (EI) calcd for C11H19NSe 245.0683, found 245.0681. Synthesis of 1-Methyl-4-pheynylpyrrolidine-2-thione24 (9a). To a solution of 1-methyl-4-phenylpyrrolidin-2-one (0.18 g, 1.0 mmol), sulfur (0.035 g, 1.1 mmol), and dibenzylamine (0.21 mL, 1.1 mmol) in toluene (1.0 mL) was added dichloromethylsilane (0.11 mL, 1.1 mmol) at rt, and the resulting suspension was heated at 115 °C for 3 h. The mixture was cooled to rt, and saturated aqueous sodium bicarbonate was added to the solution. The separated aqueous layer was extracted with CH2Cl2. The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting oil was purified by column chromatography on silica gel (hexane/AcOEt = 5:1) to give 1methyl-4-pheynylpyrrolidine-2-thione (0.14 g, 73%) as a yellow liquid: 1 H NMR (CDCl3) δ 3.20 (dd, J = 18.1, 8.3 Hz, 1H), 3.32 (s, 3H), 3.47 (dd, J = 18.1, 8.8 Hz, 1H), 3.64 (brquint, 1H), 3.77 (dd, J = 11.2, 6.8 Hz, 1H), 4.10 (dd, J = 11.2, 8.3 Hz, 1H), 7.15−7.37 (m, 5H). Synthesis of 3-Allyl-1-methyl-4-phenylpyrrolidine-2-thione (10aa). To a THF solution (1.0 mL) of LDA, generated from i-Pr2NH (0.070 mL, 0.50 mmol) and n-BuLi (1.5 M hexane solution, 0.32 mL, 0.50 mmol), was added 1-methyl-4-pheynylpyrrolidine-2-thione (0.095 g, 0.50 mmol) at 0 °C, and the mixture was stirred for 10 min at that temperature. Allyl bromide (0.035 mL, 0.41 mmol) was then added, and the mixture was stirred for 10 min at 0 °C. The mixture was poured onto brine and extracted with Et2O. The combined organic layer was dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel (hexane/AcOEt = 20:1) to give 3-allyl-1methyl-4-phenylpyrrolidine-2-thione (10aa) (0.054 g, 57%) as a pale yellow liquid: Rf = 0.37 (hexane/AcOEt = 5:1); IR (neat) 3071, 3028, 3001, 2927, 2872, 1686, 1638, 1602, 1523, 1462, 1398, 1306, 1253, 1158, 1130, 1030, 999, 916, 757, 700 cm−1; 1H NMR (CDCl3) δ 2.65 (m, 2H), 3.09 (dt, J = 12.2, 6.8 Hz, 1H), 3.32 (s, 3H), 3.35 (ddd, J = 12.2, 8.8, 7.3 Hz, 1H), 3.67 (dd, J = 11.2, 7.3 Hz, 1H), 3.98 (dd, J = 11.2, 8.8 Hz, 1H), 5.06 (d, J = 17.1 Hz, 1H), 5.10 (d, J = 10.3 Hz, 1H), 5.72 (ddt, J = 17.1, 10.3, 6.8 Hz, 1H), 7.18−7.35 (m, 5H); 13C{1H} NMR (CDCl3) δ 37.3, 38.4 44.1, 64.5, 64.7, 118.2, 127.3, 127.4, 129.1, 134.6, 141.3, 206.6; MS (EI) m/z 231 (100, M+), 190 (30, M+ − C3H5); HRMS (EI) calcd for C14H17NS 231.1082, found 231.1067. Synthesis of 3-Allyl-1-methyl-4-phenyl-3-(1-phenylallyl)pyrrolidine-2-selenone (11). To a THF solution (1.0 mL) of LDA, generated from i-Pr2NH (0.070 mL, 0.50 mmol) and n-BuLi (1.5 M hexane solution, 0.32 mL, 0.50 mmol), was added crude mixture of the synthesis of 8aa (0.5 mmol scale) at 0 °C, and the mixture was stirred for 10 min at that temperature. Cinnamyl bromide (0.081 mL, 0.41 mmol) was then added to the solution, and the mixture was stirred for 10 min at 0 °C. The mixture was poured onto brine and extracted

with Et2O. The combined organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/AcOEt = 50:1) to give 3-allyl1-methyl-4-phenyl-3-(1-phenylallyl)pyrrolidine-2-selenone (11) (0.13 g, 80% overall yield of two step) as a pale yellow powder: mp 110−140 °C dec; IR (neat) 3077, 3059, 3025, 2978, 2962, 2939, 2919, 2883, 1546, 1495, 1450, 1403, 1311, 1253, 1099, 926, 905, 768, 751, 711, 700 cm−1; 1H NMR (CDCl3) δ 2.24 (dd, J = 15.3, 8.1 Hz, 1H), 2.48−2.52 (m, 1H), 2.52 (dd, J = 12.3, 8.5 Hz, 1H,), 3.18 (s, 3H), 3.40 (dd, J = 12.3, 3.4 Hz, 1H), 3.72 (dd, J = 8.5, 3.4 Hz, 1H), 4.20 (d, J = 10.3 Hz, 1H), 4.42 (d, J = 11.7 Hz, 1H), 4.45−4.47 (m, 1H), 5.27 (d, J = 17.1 Hz, 1H), 5.30 (d, J = 9.9 Hz, 1H), 5.68−5.78 (m, 1H), 6.40 (ddd, J = 17.1, 10.3, 9.9 Hz, 1H), 7.08−7.56 (m, 10H); 13C{1H} NMR (CDCl3) δ 38.2, 41.8, 44.5, 57.8, 63.8, 69.0, 115.3, 119.5, 127.3, 127.4, 128.0, 128.4, 129.0, 129.1, 134.1, 135.3, 140.2, 140.8, 209.2; 77Se NMR (CDCl3) δ 400.4; MS (EI) m/z 395 (58, M(79Se)+), 393 (29, M(77Se)+), 391 (13, M(75Se)+), 354 (35, M+ − C3H5), 278 (63, M+ − C9H9), 237 (7, M+ − C12H14), 117 (74, M+ − C14H16NSe); HRMS (EI) calcd for C23H25NSe 395.1152, found 395.1141. Reaction of Li-enolate of 1-Methylpyrrolidin-2-one and Crotyl Chloride. To a THF solution (2.0 mL) of LDA, generated from i-Pr2NH (0.13 mL, 1.0 mmol) and n-BuLi (1.5 M hexane solution, 0.64 mL, 1.0 mmol), was added 1-methylpyrrolidin-2-one (0.99 g, 1.0 mmol) at 0 °C, and the mixture was stirred for 10 min at this temperature. Crotyl chloride (0.078 mL, 0.80 mmol) was then added, and the mixture was stirred for 10 min at 0 °C. The mixture was poured into brine and extracted with Et2O. The combined organic layer was dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel (hexane/AcOEt = 5:1) to give a diastereomer mixture of 3-(but-2-en-1-yl)-1-methylpyrrolidin-2-one (12) (0.44 g, 36%, major/minor = 81:19) as a colorless liquid: 1H NMR (CDCl3) δ 1.61 (d, J = 6.3 Hz, 3H), 1.64−1.73 (m, 1H), 2.05− 2.11 (m, 2H), 2.43 (m, 2H), 2.80 (s, 3H), 3.24 (brt, 2H), 5.33(m, 1H), 5.46 (dq, J = 14.6, 6.3 Hz, 1H). Synthesis of 1,2,2,3-Tetraallyl-4-phenylpyrrolidine (13a). To an Et2O (1.3 mL) solution of 1,3-diallyl-4-phenylpyrrolidine-2selenone (0.078 g, 0.26 mmol) was added allylmagnesium bromide (1.0 M Et2O solution, 0.78 mL, 0.78 mmol) at 0 °C, and the mixture was stirred for 2 h at room temperature. The mixture was poured onto satuated aquesous solution of NH4Cl, extracted with Et2O, and washed with brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/AcOEt = 50:1) to give 1,2,2,3-tetraallyl-4-phenylpyrrolidine (13a) (0.67 g, 82%) as a pale yellow liquid: Rf = 0.80 (hexane/ AcOEt = 5:1); IR (neat) 3074, 3027, 3006, 2976, 2921, 2800, 1638, 1602, 1494, 1445, 1415, 1346, 1262, 995, 911, 757, 700 cm−1; 1H NMR (CDCl3) δ 2.03−2.28 (m, 6H), 2.34 (dd, J = 14.2, 4.9 Hz, 1H, PhCHCH2N), 2.83 (d, J = 4.9 Hz, 2H), 2.98−3.09 (m, 2H), 3.33 (dd, J = 13.7, 4.9 Hz, 1H), 4.76−5.10 (m, 8H), 5.38 (ddt, J = 14.3, 10.3, 6.3 Hz, 1H), 5.74 (ddt, J = 16.7, 10.3, 6.3 Hz, 1H), 5.84−6.01 (m, 2H), 7.07−7.20 (m, 5H); 13C{1H} NMR (CDCl3) δ 34.8, 38.4, 40.1, 48.6, 51.2, 53.4, 59.5, 66.7, 115.0, 115.2, 117.0, 117.3, 126.0, 128.0, 128.2, 145.7, 135.3, 136.3, 137.4, 138.0; MS (EI) m/z 307 (7, M+), 306 (27, M+ − H), 267 (72, M+ − C3H5); HRMS (EI) calcd for C22H28N 306.2222, found 306.2209. Synthesis of 1,2,2-Triallyl-3-(2-methylbut-3-en-2-yl)-4-phenylpyrrolidine (13b). To an Et2O (0.50 mL) solution of 3-benzyl-1methyl-3-(2-methylbut-3-en-2-yl)-4-phenylpyrrolidine-2-selenone (0.033 g, 0.10 mmol) was added allylmagnesium bromide (1.0 M Et2O solution, 0.30 mL, 0.30 mmol) at 0 °C, and the mixture was stirred for 2 h at room temperature. The mixture was poured into satuated aquesous solution of NH4Cl, washed with brine, and extracted with Et2O. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/ AcOEt = 50:1) to give 1,2,2-triallyl-3-(2-methylbut-3-en-2-yl)-4phenylpyrrolidine (13b) (0.23 g, 71%) as a pale yellow liquid: Rf = 0.62 (hexane/AcOEt = 5:1); IR (neat) 3032, 2925, 2852, 1672, 1604, 1496, 1433, 1413, 1363, 1197, 1130, 829, 798, 756, 719, 703, 665 cm−1; 1 H NMR (CDCl3) δ 0.82 (s, 3H), 0.87 (s, 3H), 2.17 (dd, J = 14.1, 7.8 Hz, 1H), 2.30 (dd, J = 15.6, 9.3 Hz, 1H), 2.35 (d, J = 9.3 Hz, 1H), 2.45 3086

DOI: 10.1021/acs.joc.8b00306 J. Org. Chem. 2018, 83, 3078−3089

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(dd, J = 14.1, 6.8 Hz, 1H), 2.59 (dd, J = 15.6, 3.4 Hz, 1H), 2.73 (dd, J = 9.7, 3.4 Hz, 1H), 2.88 (dd, J = 14.1, 7.3 Hz, 1H), 2.95 (brt, 1H), 3.15 (td, J = 9.3, 3.4 Hz, 1H), 3.42 (dd, J = 14.1, 2.4 Hz, 1H), 4.84−5.14 (m, 8H), 5.60−5.69 (m, 1H, CH2CH), 5.85−6.10 (m, 3H), 7.05−7.26 (m, 5H); 13C{1H} NMR (CDCl3) δ 29.6, 29.7, 37.4, 38.6, 40.1, 43.4, 51.3, 59.2, 60.8, 68.7, 110.4, 115.0, 117.1, 117.3, 125.5, 127.6, 128.2, 136.0, 136.5, 137.6, 147.3, 150.3; MS (EI) m/z 335 (100, M+); HRMS (EI) calcd for C24H33N 335.2613, found 335.2613. Synthesis of 1,2,2,3-Tetraallylpiperidine (13c). To an Et2O (1.5 mL) solution of 1,3-diallylazepane-2-selenone (0.074 g, 0.30 mmol) was added allylmagnesium bromide (0.57 M Et2O solution, 1.6 mL, 0.90 mmol) at 0 °C, and the mixture was stirred for 2 h at room temperature. The mixture was poured onto satuated aquesous solution of NH4Cl, extracted with Et2O, and washed with brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/AcOEt = 50:1) to give 1,2,2,3-tetraallylpiperidine (0.057g, 78%) as a pale yellow liquid: Rf = 0.83 (hexane/AcOEt = 5:1); IR (neat) 3074, 2928, 2856, 2801, 1638, 1438, 1383, 1260, 1097, 995, 909, 804 cm−1; 1H NMR (CDCl3) δ 1.25 (m, 1H), 1.35−1.47 (m, 1H), 1.52−1.75 (m, 4H), 2.08 (dd, J = 14.8, 6.7 Hz, 1H), 2.30 (m, 2H), 2.43−2.59 (m, 3H), 2.67 (dt, J = 12.1, 4.0 Hz, 1H), 2.78 (dd, J = 14.8, 7.6 Hz, 1H), 3.48 (brt, 1H), 4.93−5.14 (m, 8H), 5.64−5.75 (m, 2H), 5.84−5.96 (m, 2H); 13C{1H} NMR (CDCl3) δ 24.9, 25.0, 34.0, 35.6, 37.1, 41.7, 46.1, 53.1, 61.2, 115.0, 115.3, 116.5, 116.9, 135.1, 136.2, 138.1, 138.4; MS (EI) m/z 245 (100, M+); HRMS (EI) calcd for C17H27N 245.2143, found 245.2149. Synthesis of 1,2,2,3-Tetraallylazepane (13d). To an Et2O (1.5 mL) solution of 1,3-diallylazepane-2-selenone (0.069 g, 0.27 mmol) was added allylmagnesium bromide (0.57 M Et2O solution, 1.4 mL, 0.81 mmol) at 0 °C, and the mixture was stirred for 2 h at room temperature. The mixture was poured onto saturated aqueous solution of NH4Cl, washed with brine, and extracted with Et2O. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/AcOEt = 50:1) to give 1,2,2,3-tetraallylazepane (0.058 g, 83%) as a pale yellow liquid: Rf = 0.83 (hexane/AcOEt = 5:1); IR (neat) 3074, 3004, 29765, 2925, 2855, 2805, 1825, 1638, 1453, 1415, 1344, 1265, 1167, 1105, 994, 910 cm−1; 1H NMR (CDCl3) δ 1.04 (ddd, J = 13.0, 5.4, 2.7 Hz, 1H), 1.25 (ddd, J = 13.0, 4.9, 3.1 Hz, 1H), 1.28−1.35 (m, 1H), 1.50−1.54 (m, 1H), 1.63−1.74 (m, 2H), 1.82−1.92 (m, 2H), 2.18 (m, 1H), 2.25− 2.39 (m, 4H), 2.49 (dt, J = 14.3, 3.6 Hz, 1H), 2.96 (dd, J = 13.9, 10.3 Hz, 1H), 3.03 (dd, J = 13.9, 8.5 Hz, 1H), 3.60 (dt, J = 14.3, 1.8 Hz, 1H), 4.95−5.18 (m, 8H), 5.71−6.13 (m, 4H); 13C{1H} NMR (CDCl3) δ 28.3, 29.7, 31.6, 37.9, 39.5, 41.2, 46.6, 47.7, 54.2, 63.4, 115.1, 115.2, 115.5, 117.0, 136.3, 137.3, 138.7, 139.4; MS (EI) m/z 259 (41, M+), 218 (100, M− -C3H5), 177 (39, M+ − C6H10); HRMS (EI) calcd for C18H29N 259.2300, found 259.2302. Synthesis of 2,3-Diallyl-1-methyl-2-((trimethylsilyl)ethynyl)pyrrolidine (14). To an Et2O (2.5 mL) solution of 3-allyl-1methylpiperidine-2-selenone (0.11 g, 0.50 mmol) was added methyl triflate (0.056 mL, 0.50 mmol) at rt, and the mixture was stirred at that temperature for 30 s. To this was added lithium acetylide prepared from (trimethylsilyl)acetylene (0.14 mL, 1.0 mmol) and n-BuLi (1.5 M hexane solution, 0.65 mL, 1.0 mmol) in Et2O (2.5 mL) at 0 °C, and the resulting mixture was stirred for 0.5 h at rt. Then, allylmagnesium bromide (1.0 M THF solution, 3.0 mL, 3.0 mmoL) was added to the solution, and the resulting mixture was stirred for 3 h at this temperature. The resulting mixture was poured onto a saturated aqueous solution of NH4Cl, extracted with Et2O, and washed with brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/AcOEt = 20:1) to give 2,3-diallyl-1-methyl-2((trimethylsilyl)ethynyl)pyrrolidine (14) (0.056 g, 43%, dr = 85:15) as a pale yellow liquid: Rf = 0.50 (hexane/AcOEt = 5:1); IR (neat) 3076, 2960, 2787, 2153, 1640, 1450, 1384, 1348, 1250, 1092, 995, 912, 842, 759, 699 cm−1; 1H NMR (CDCl3) δ 0.16 (s, 2H), 0.17 (s, 7H), 1.33−1.42 (m, 0.8H), 1.49−1.60 (m, 0.2H), 1.87−1.99 (m, 1.2H), 2.01−2.21 (m, 1.8H), 2.27 (s, 1.7H), 2.28 (s, 1.3H), 2.33−2.50 (m, 4H), 2.95 (m, 0.8H), 3.00 (m, 0.2H), 4.95−5.12 (m, 4H), 5.69−5.98 (m, 2H); 13C{1H} NMR (CDCl3) δ 0.15, 0.19, 26.1, 27.3, 34.4, 35.4,

36.2, 36.4, 38.6, 40.1, 44.8, 46.9, 52.3, 52.8, 66.97, 66.99, 92.53, 92.57, 102.92, 102.97, 115.4, 116.0, 117.3, 117.7, 133.4, 134.6, 137.3, 137.4; MS (EI) m/z 261 (100, M+), 220 (61, M+ − C3H5), 164 (26, M+ − C5H9Si); HRMS (EI) calcd for C16H27NSi 261.1913, found 261.1910. Synthesis of 7-Phenyl-1,4,7,7a,8,11-hexahydro-6H-pyrido[2,1-i]indole (15a). A solution of 1,2,2,3-tetraallyl-4-phenylpyrrolidine (0.046 g, 0.15 mmol) in toluene (3.0 mL) was treated with trifluoroacetic acid (0.013 mL, 0.17 mmol) and second-generation Grubbs catalyst (0.017 g, 0.020 mmol). The resulting solution was heated to 100 °C for 1 h by microwave irradiation. The mixture was then filtered through a pad of Celite and concentrated in vacuo. The thus obtained residue was purified by gel permeation chromatography to give 7-phenyl-1,4,7,7a,8,11-hexahydro-6H-pyrido[2,1-i]indole (15a) (0.034 g, 91%) as a pale yellow liquid. Caution: The product easily decomposes on silica gel: IR (neat) cm−1 3032, 2925, 2852, 1672, 1496, 1433, 1413, 1197, 1130, 829, 798, 756, 719, 703, 665; 1H NMR (CDCl3) δ 2.01−2.05 (m, 1H), 2.18−2.41 (m, 4H), 2.48−2.54 (m, 0.5H), 2.65−2.69 (m, 0.5H), 2.85−2.95 (m, 1H), 3.20−3.33 (m, 1H), 3.38−3.44 (m, 1H), 3.48−3.55 (m, 0.5H), 3.67−3.71 (m, 0.5H), 3.88− 3.97 (m, 1H), 4.03−4.18 (m, 1H), 5.61−5.97 (m, 4H), 7.24−7.44 (m, 5H); 13C{1H} NMR (CDCl3) δ 22.1, 23.6, 24.0, 25.8, 32.5, 32.6, 42.9, 45.0, 45.2, 45.5, 48.3, 50.8, 55.8, 56.9, 63.4, 63.5, 117.4, 120.3, 120.5, 123.4, 123.5, 124.6, 125.6, 126.6, 126.2, 127.5, 127.6, 128.2, 129.0, 129.1, 129.2, 129.3; MS (EI) m/z 251 (100, M+); HRMS (EI) calcd for C18H21N 251.1674, found 251.1671. Further characterization details including the H−H COSY spectrum are included in the Supporting Information. Synthesis of 1,4,6,7,8,8a,9,12-Octahydropyrido[2,1-j]quinoline (15c). A solution of 1,2,2,3-tetraallylpiperidine (0.037 g, 0.15 mmol) in toluene (3.0 mL) was treated with trifluoroacetic acid (0.013 mL, 0.17 mmol) and second-generation Grubbs catalyst (0.017 g, 0.020 mmol). The resulting solution was heated to 100 °C for 1 h by microwave irradiation. The mixture was then filtered through a pad of Celite and concentrated in vacuo. The thus-obtained residue was purified by gel permeation chromatography to give 1,4,6,7,8,8a,9,12octahydropyrido[2,1-j]quinoline (15c) (0.013 g, 44%) as a pale yellow liquid. Caution: The product easily decomposes on silica gel: IR (neat) 3036, 2932, 1671, 1446, 1408, 1383, 1196, 1167, 1125, 1073, 1051, 1037, 827, 795, 719, 666 cm−1; 1H NMR (CDCl3) δ 1.36−1.47 (m, 1H), 1.53−1.59 (m, 1H), 1.67−1.94 (m, 4H), 2.15−2.45 (m, 6H), 2.60−2.69 (m, 1H), 3.02−3.48 (m, 2H), 5.50−5.86 (m, 4H); 13C{1H} NMR (CDCl3) δ 21.6, 22.1, 22.3, 22.6, 24.8, 25.5, 29.2, 29.5, 32.4, 32.6, 37.3, 37.5, 47.9, 48.2, 49.3, 49.6, 59.6, 59.9, 118.1, 119.1, 120.3, 122.8, 123.2, 124.8, 125.9; MS (EI) m/z 189 (100, M+); HRMS (EI) calcd for C13H19N 189.1517, found 189.1522. Synthesis of 4,4a,5,6,7,8,10,13-Octahydro-1H-benzo[b]pyrido[1,2-a]azepine (15d). A solution of 1,2,2,3-tetraallylazepane (0.039 g, 0.15 mmol) in toluene (3.0 mL) was treated with trifluoroacetic acid (0.013 mL, 0.17 mmol) and second-generation Grubbs catalyst (0.017 g, 0.020 mmol). The resulting solution was heated to 100 °C for 1 h by microwave irradiation. The mixture was then filtered through a pad of Celite and concentrated in vacuo. The thus obtained residue was purified by gel permeation chromatography to give 4,4a,5,6,7,8,10,13-octahydro-1H-benzo[b]pyrido[1,2-a]azepine (15d) (0.017 g, 56%) as a pale yellow liquid. Caution: The product easily decomposes on silica gel: IR (neat) 3033, 2932, 2361, 1671, 1455, 1426, 1199, 1129, 828, 798, 719, 670 cm−1; 1H NMR (CDCl3) δ 1.34−1.47 (m, 2H), 1.59−2.06 (m, 6H), 2.20−2.56 (m, 5H), 2.76 (brd, 1H, NCH2CH), 2.98 (brd, 1H), 3.19−3.47 (m, 2H), 5.49−5.89 (m, 4H); 13C{1H} NMR (CDCl3) δ 22.0, 22.1 (CH2), 24.9, 25.0, 26.5, 26.6, 27.8, 28.1, 28.8, 29.0, 32.3, 32.5, 43.1, 43.3, 51.0, 51.2, 51.5, 51.7, 63.1, 64.0, 119.7, 120.3, 122.1, 123.1, 125.1, 125.3, 126.0, 128.0; MS (EI) m/z 203 (25, M+); HRMS (EI) calcd for C14H21N 203.1674, found 203.1683.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00306. 3087

DOI: 10.1021/acs.joc.8b00306 J. Org. Chem. 2018, 83, 3078−3089

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(8) For examples of the synthesis of cocculolidine, see: (a) Isobe, K.; Mohri, K.; Maeda, M.; Takeda, T.; Tsuda, Y. Chem. Pharm. Bull. 1987, 35, 2602. (b) Kawasaki, T.; Onoda, N.; Watanabe, H.; Kitahara, T. Tetrahedron Lett. 2001, 42, 8003. (9) For recent examples of the synthesis of cephalotaxine, see: (a) Ouyang, J.; Mi, X.; Wang, Y.; Hong, R. Synlett 2017, 28, 762. (b) Ma, G.-Z.; Li, P.-F.; Liu, L.; Li, W.-D. Z.; Chen, L. Org. Lett. 2017, 19, 2250. (c) Ma, X.-Y.; An, X.-T.; Zhao, X.-H.; Du, J.-Y.; Deng, Y.-H.; Zhang, X.-Z.; Fan, C.-A. Org. Lett. 2017, 19, 2965. (10) For recent examples on the synthesis of erythrocarine, see: (a) Shimizu, K.; Takimoto, M.; Mori, M. Org. Lett. 2003, 5, 2323. (b) Shimizu, K.; Takimoto, M.; Sato, Y.; Mori, M. J. Organomet. Chem. 2006, 691, 5466. (c) Wang, Q.; Padwa, A. Org. Lett. 2006, 8, 601. (11) For selected reviews on the RCM of heteroatom-containing compounds, see: (a) Arisawa, M.; Nishida, A.; Nakagawa, M. J. Organomet. Chem. 2006, 691, 5109. (b) Clark, J. S. Chem. Commun. 2006, 3571. (c) Kuznetsov, N. Y.; Bubnov, Y. N. Russ. Chem. Rev. 2015, 84, 758. For examples of synthetic routes to polycyclic amines by RCM, see the references cited in these articles. (12) For selected reviews, see: (a) Ojima, I.; Moralee, A. C.; Vassar, V. C. Top. Catal. 2002, 19, 89. (b) Gibson, S. E.; Stevenazzi, A. Angew. Chem., Int. Ed. 2003, 42, 1800. (c) Shibata, T. Adv. Synth. Catal. 2006, 348, 2328. (d) Kitagaki, S.; Inagaki, F.; Mukai, C. Chem. Soc. Rev. 2014, 43, 2956. (13) (a) Murai, T.; Nogawa, S.; Mutoh, Y. Bull. Chem. Soc. Jpn. 2007, 80, 2220. For examples of the corresponding reactions with thioamides, see: (b) Murai, T.; Mutoh, Y.; Ohta, Y.; Murakami, M. J. Am. Chem. Soc. 2004, 126, 5968. (c) Murai, T.; Toshio, R.; Mutoh, Y. Tetrahedron 2006, 62, 6312. (d) Murai, T.; Asai, F. J. Am. Chem. Soc. 2007, 129, 780. (14) (a) Tamaru, Y.; Furukawa, Y.; Mizutani, M.; Kitao, O.; Yoshida, Z. J. Org. Chem. 1983, 48, 3631. (b) Beslin, P.; Perrio, S. Tetrahedron 1991, 47, 6275. (c) Beslin, P.; Perrio, S. Tetrahedron 1992, 48, 4135. (d) Beslin, P.; Perrio, S. Tetrahedron 1993, 49, 3131. (e) Sreekumar, R.; Padmakumar, R. Tetrahedron Lett. 1997, 38, 2413. (f) Beslin, P.; Lelong, B. Tetrahedron 1997, 53, 17253. (g) Wang, L.; Li, B.; Jin, Q.; Guo, Z.; Tang, S.; Ding, D. J. Mol. Catal. A: Chem. 2000, 160, 377. (15) DFT calculations at the B3LYP/6-311+G** level of theory suggested energy barriers ΔG⧧ for the rearrangement leading to the respective diastereomers of 8cd of >26 kcal/mol (see Table S1). This reaction should thus hardly proceed under ambient conditions. These results also indicate that 8cd should be more labile than the corresponding precursor allyl eneselenol ether Pre-8cd. Accordingly, the reaction did not reach completion due to an equilibrium, and the remaining Pre-8cd underwent hydrolysis upon quenching. This notion is supported by the formation of a significant amount of the corresponding (oxo)lactam of 7c in this reaction. (16) For full details, see the Supporting Information. (17) For an example of the α-allylation of lactams via Li-enolates, see: Trost, B. M.; Zhang, Y. Chem. - Eur. J. 2011, 17, 2916. (18) Shibahara, F.; Suenami, A.; Yoshida, A.; Murai, T. Chem. Commun. 2007, 2354. (19) There are virtually no energy barriers for the rotation of the allyl group on the selenium atom in allyl eneselenol ethers such as Pre-(S,S)8aa to give Pre-(R,S)-8aa (cf. Figure 6). Thus, the generation of all diastereomers regarding the stereochemistry at the α- and β-position is assumed to proceed from the most stable configuration of the allyl eneselenol ethers. Similar discussions have been brought forward for the thio-Claisen rearrangement; see ref 5a. (20) Senter, T. J.; Schulte, M. L.; Konkol, L. C.; Wadzinski, T. E.; Lindsley, C. W. Tetrahedron Lett. 2013, 54, 1645. (21) For the temperature dependence of the 1H NMR spectra of 15a, see the Supporting Information. Unfortunately, 15a,c,d are relatively unstable and decompose readily under ambient conditions, particularly on silica gel or under acidic conditions. Therefore, the structures of these compounds have not yet been determined unequivocally. However, the 2D H−H COSY NMR spectrum of 15a clearly suggested a primary structure that is identical to that shown in Scheme 5.

Computational details and X-ray diffraction analysis (PDF) Characterization details for 15a (PDF) 1 H and 13C{1H} NMR of novel compounds (PDF) X-ray data for compound 8cb (CIF) X-ray data for compound 11 (CIF)

AUTHOR INFORMATION

Corresponding Authors

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

Fumitoshi Shibahara: 0000-0003-2889-140X Toshiaki Murai: 0000-0003-4945-0996 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for the support from JSPS, a Grant-in-Aid for Scientific Research (16K05769). Parts of the computations were performed using resources of the Research Center for Computational Science, Okazaki, Japan. We thank Prof. Toshiyasu Inuzuka for helpful suggestions and instructions regarding the measurements of 2D NMR spectra as well as Mr. Toshifumi Maruyama for carrying out single-crystal X-ray diffraction measurements.

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REFERENCES

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