A new method for the synthesis of 2,2-dimethyl-6-substituted 4-piperidone was developed; two equivalents of acetone were annulated with N-unsubstituted imines in-situ generated from benzyl azides using a ruthenium catalyst in the presence of L-proline.X113Ysciescopu

Han, J

Park, J

Rhee, YH

Bulletin of the Korean Chemical Society

포항공과대학교

Synthesis of Piperidones  Bull. Korean Chem. Soc. 2014, Vol. 35, No. 12     3433http://dx.doi.org/10.5012/bkcs.2014.35.12.3433Synthesis of Piperidones from Benzyl Azides and AcetoneJunghoon Han, Young Ho Rhee,* and Jaiwook Park* Department of Chemistry, Pohang University of Science and Technology, Pohang 790-784, Korea*E-mail: pjw@postech.ac.kr (J. Park); yhrhee@postech.edu (Y.H. Rhee)Received July 21, 2014, Accepted August 4, 2014A new method for the synthesis of 2,2-dimethyl-6-substituted 4-piperidone was developed; two equivalents ofacetone were annulated with N-unsubstituted imines in-situ generated from benzyl azides using a rutheniumcatalyst in the presence of L-proline. Key Words : 4-Piperidone, N-Unsubstituted imine, Benzyl azide, Synthetic methodIntroductionAlthough there are many methods for the synthesis of 4-piperidones,1 those for 2,2,6-trisubstituted ones are rare.Noticeably, Chan and co-workers found a unprecedentedtandem Mannich reaction to afford 2,2-dimethyl-6-sub-stitued 4-piperidones when they tried the direct aldol reac-tion of aldehydes with acetone in ammonia solution.2 Theysuggested imines as the key intermediates for the formationof 4-piperidones (Scheme 1). Curiously, the 4-piperidones are formed as the major pro-ducts in the reaction of acetone with hydroxybenzaldehydes,pyrrole-2-carbaldehyde, and indol-3-carbaldehyde in a solu-tion of ammonia in methanol. Later they could extend thesubstrate scope by employing ionic liquid as the solvent andL-proline as an organocatalyst.3 However, excess NH3 isneeded also for this protocol, which is added by bubblingammonia gas into the ionic liquid. The preferential occurr-ence of Mannich reaction over aldol reaction was explainedby the role of ionic liquid enhancing the formation of imineintermediates. Recently, we reported a novel Ru-catalyzed transforma-tion of alkyl azides into N-unsubstituted imines,4 which hadbeen known as unstable intermediates in general.5 Duringour investigation about synthetic utility of N-unsubstitutedimines,6 we envisioned that the synthesis of 2,2-dimethyl-6-substitued 4-piperidones would be possible by employing N-H aldimines generated by our catalytic reaction. This alter-native synthetic method will avoid the use of ammonia gas,enable the use of organic azides instead of aldehydes, andextend the scope of 4-piperidone products. Here we report asimple and one-pot protocol for the synthesis of 2,2-di-methyl-6-substituted 4-piperidones under mild conditions, inwhich N-H imines are directly generated from benzyl azidesby a Ru-catalyzed reaction (Scheme 2). ExperimentalGeneral Information. Air-sensitive manipulations werecarried out with standard Schlenk techniques under argonatmosphere. Commercial chemicals were used without furtherpurification. Flash column chromatography was carried outon silica gel (230-400 mesh) as the stationary phase. 1H and13C NMR spectra were recorded with Bruker (300 MHz)spectrometer. 1H NMR spectra were referenced to residualCDCl3 (7.26 ppm) and reported as follows; chemical shift,multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,quint = quintet, m = multiplet). Chemical shift of 13C NMRspectra were measured relative to CDCl3 (77.23) ppm. Infrar-ed spectra were recorded on a Shimadzu IR-470 spectro-meter with KBr pellets. Mass spectral data were obtainedfrom the Korea Basic Science Institute (Daegu) on a JeolJMS 700 high resolution mass spectrometer.General Procedure for the Synthesis of 2,2-Dimethyl 6-Substituted 4-Piperidones from Benzyl Azide and Acetone.A solution of an azide (0.25 mmol), 1 (2.0 mol %), and L-proline (100 mol %) in acetone (0.50 mL) and DMSO (2.0mL) was stirred at room temperature with illumination of 30W fluorescent light for 12 h under argon atmosphere. Theresulting mixture was extracted with dichloromethane (10mL × 3). Combined organic layer was washed with brine,dried over Na2SO4, and filtered. The filtrate was concentrat-ed by a rotary evaporator, and the residue was purified byflash column chromatography using silica gel.Product 3a, 3b, 3f, 3g, 3h, 3o, and 3q are knowncompounds.3Scheme 1. A suggested pathway involving imine intermediates forthe formation of 2,2-dimethyl-6-substitued 4-piperidones.Scheme 2. Synthetic methods for 2,2-dimethyl-6-substitued 4-piperidones.3434     Bull. Korean Chem. Soc. 2014, Vol. 35, No. 12 Junghoon Han et al.6-(4-Methoxyphenyl)-2,2-dimethylpiperidin-4-one (3a).1H NMR (CDCl3, 300 MHz) δ 7.34-7.32 (m, 2H), 6.90-6.87(m, 2H), 4.16 (dd, J = 4.3, 10.5 Hz, 1H), 3.80 (s, 3H), 2.48-2.23 (m, 4H), 1.50 (br, 1H), 1.31 (s, 3H), 1.19 (s, 3H); 13CNMR (CDCl3, 75 MHz) δ 209.8, 159.2, 135.2, 127.8, 114.1,55.5, 55.4, 54.3, 53.9, 50.0, 32.2, 25.5.2,2-Dimethyl-6-phenylpiperidin-4-one (3b). 1H NMR(CDCl3, 300 MHz) δ 7.43-7.26 (m, 5H), 4.22 (dd, J = 3.9,11.0 Hz, 1H), 2.54-2.25 (m, 4H), 1.50 (bs, 1H), 1.32 (s, 3H),1.20 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 209.7, 143.0,128.8, 127.9, 126.7, 56.1, 54.3, 54.1, 49.9, 32.3, 25.6.2,2-Dimethyl-6-o-tolylpiperidin-4-one (3c). 1H NMR(CDCl3, 300 MHz) δ 7.57-7.54 (m, 1H), 7.27-7.12 (m, 3H),4.43 (dd, J = 6.5, 8.3 Hz, 1H), 2.46-2.41 (m, 3H), 2.37 (s,3H), 2.32-2.28 (m, 1H), 1.37 (bs, 1H), 1.32 (s, 3H), 1.22 (s,3H); 13C NMR (CDCl3, 75 MHz) δ 210.0, 140.7, 135.4,130.7, 127.5, 126.7, 125.5, 54.5, 54.2, 51.6, 48.4, 32.3, 25.4,19.2. IR (cm−1): 3306, 2964, 1711, 1464, 1288, 1248, 751.HRMS (EI+) 217.1469 (calcd for C14H19NO 217.1467).2,2-Dimethyl-6-m-tolylpiperidin-4-one (3d). 1H NMR(CDCl3, 300 MHz) δ 7.27-7.18 (m, 3H), 7.11-7.09 (m, 1H),4.17 (dd, J = 4.2, 10.6 Hz, 1H), 2.48-2.40 (m, 3H), 2.36 (s,3H), 2.30-2.26 (m, 1H), 1.53 (bs, 1H), 1.32 (s, 3H), 1.20 (s,3H); 13C NMR (CDCl3, 75 MHz) δ 209.7, 142.9, 138.5,128.7, 128.6, 127.3, 123.7, 56.1, 54.3, 54.0, 49.8, 32.3, 25.5,21.5. IR (cm−1): 3305, 2964, 1713, 1608, 1489, 1412, 1287,1238, 813, 701. HRMS (EI+) 217.1465 (calcd for C14H19NO217.1467).2,2-Dimethyl-6-p-tolylpiperidin-4-one (3e). 1H NMR(CDCl3, 300 MHz) δ 7.31-7.28 (m, 2H), 7.17-7.15 (m, 2H),4.18 (dd, J = 4.1, 10.7 Hz, 1H), 2.51-2.40 (m, 3H), 2.34 (s,3H), 2.29-2.24 (m, 1H), 1.52 (bs, 1H), 1.31 (s, 3H), 1.19 (s,3H); 13C NMR (CDCl3, 75 MHz) δ 209.8, 140.1, 137.5,129.4, 126.6, 55.8, 54.3, 54.0, 49.9, 32.3, 25.5, 21.2. IR(cm−1): 3308, 2964, 1710, 1474, 1288, 1247, 760. HRMS(EI+) 217.1466 (calcd for C14H19NO 217.1467).6-(4-Fluorophenyl)-2,2-dimethylpiperidin-4-one (3f).1H NMR (CDCl3, 300 MHz) δ 7.41-7.37 (m, 2H), 7.06-7.01(m, 2H), 4.20 (dd, J = 3.6, 11.2 Hz, 1H), 2.50-2.24 (m, 4H),1.47 (bs, 1H), 1.32 (s, 3H), 1.20 (s, 3H); 13C NMR (CDCl3,75 MHz) δ 209.4, 162.4 (d, J = 245 Hz), 139.0 (d, J = 3.2Hz), 128.4 (d, J = 7.9 Hz), 115.7 (d, J = 21.2 Hz), 55.5, 54.3,54.1, 50.1, 32.3, 25.6.6-(4-Chlorophenyl)-2,2-dimethylpiperidin-4-one (3g).1H NMR (CDCl3, 300 MHz) δ 7.38-7.35 (m, 2H), 7.33-7.30(m, 2H), 4.19 (dd, J = 3.6, 11.2 Hz, 1H), 2.50-2.24 (m, 4H),1.45 (bs, 1H), 1.32 (s, 3H), 1.19 (s, 3H); 13C NMR (CDCl3,75 MHz) δ 209.1, 141.6, 133.5, 128.9, 128.1, 55.5, 54.2,54.0, 49.8, 32.2, 25.5.6-(4-Bromophenyl)-2,2-dimethylpiperidin-4-one (3h).1H NMR (CDCl3, 300 MHz) δ 7.49-7.46 (m, 2H), 7.32-7.27(m, 2H), 4.18 (dd, J = 3.5, 11.3 Hz, 1H), 2.49-2.24 (m, 4H),1.49 (bs, 1H), 1.32 (s, 3H), 1.19 (s, 3H) ; 13C NMR (CDCl3,75 MHz) δ 209.1, 142.1, 131.9, 128.4, 121.5, 55.5, 54.1,54.0, 49.8, 32.2, 25.5.4-(6,6-Dimethyl-4-oxopiperidin-2-yl)benzonitrile (3i).1H NMR (CDCl3, 300 MHz) δ 7.67-7.64 (m, 2H), 7.58-7.55(m, 2H), 4.28 (dd, J = 3.4, 11.5 Hz, 1H), 2.52-2.26 (m, 4H),1.54 (bs, 1H), 1.34 (s, 3H), 1.21 (s, 3H); 13C NMR (CDCl3,75 MHz) δ 208.4, 148.5, 132.7, 127.6, 118.8, 111.7, 55.8,54.2, 54.1, 49.5, 32.3, 25.6. IR (cm−1): 3309, 2965, 2227,1710, 1479, 1295, 1242, 845. HRMS (EI+) 228.1263 (calcdfor C14H16N2O 228.1263).2,2-Dimethyl-6-(4-nitrophenyl)piperidin-4-one (3j). 1HNMR (CDCl3, 300 MHz) δ 8.22-8.20 (m, 2H), 7.64-7.61 (m,2H), 4.34 (dd, J = 3.4, 11.5 Hz, 1H), 2.54-2.28 (m, 4H), 1.54(bs, 1H), 1.36 (s, 3H), 1.22 (s, 3H); 13C NMR (CDCl3, 75MHz) δ 208.3, 150.5, 147.7, 127.7, 124.2, 55.7, 54.3, 54.2,49.6, 32.3, 25.6. IR (cm−1): 3319, 2965, 1708, 1597, 1488,1442, 1408, 1383, 1369, 1346, 1323, 814, 698 HRMS (EI+)248.1162 (calcd for C13H16N2O3 248.1161).6-(4-Acetylphenyl)-2,2-dimethylpiperidin-4-one (3k).1H NMR (CDCl3, 300 MHz) δ 7.97-7.94 (m, 2H), 7.54-7.52(m, 2H), 4.28 (dd, J = 3.5, 11.3 Hz, 1H), 2.60 (s, 3H), 2.53-2.27 (m, 4H), 1.56 (bs, 1H), 1.35 (s, 3H), 1.22 (s, 3H); 13CNMR (CDCl3, 75 MHz) δ 208.9, 197.7, 148.3, 136.7, 128.9,126.9, 55.8, 54.2, 54.1, 49.6, 32.2, 26.7, 25.5. IR (cm−1)3308, 2965, 1709, 1682, 1573, 1293, 1269, 1248, 839.HRMS (EI+) 245.1416 (calcd for C15H19NO2 245.1416).Methyl 4-(6,6-Dimethyl-4-oxopiperidin-2-yl)benzoate(3l). 1H NMR (CDCl3, 300 MHz) δ 8.04-8.01 (m, 2H), 7.51-7.49 (m, 2H), 4.27 (dd, J = 3.5, 11.3 Hz, 1H), 3.92 (s, 3H),2.53-2.26 (m, 4H), 1.55 (bs, 1H), 1.34 (s, 3H), 1.21 (s, 3H);13C NMR (CDCl3, 75 MHz) δ 208.9, 166.8, 148.1, 130.1,129.7, 126.7, 55.8, 54.2, 54.1, 52.2, 49.6, 32.2, 25.5. IR(cm−1): 3312, 2962, 1719, 1612, 1577, 1282, 1248, 965.HRMS (EI+) 261.1363 (calcd for C15H19NO3 261.1365).Ethyl 6,6-Dimethyl-4-oxopiperidine-2-carboxylate (3m).1H NMR (CDCl3, 300 MHz) δ 4.22 (q, J = 7.2 Hz, 2H), 3.86(dd, J = 3.7, 11.7 Hz, 1H), 2.66-2.29 (m, 4H), 1.92 (bs, 1H),1.33 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H), 1.10 (s, 3H); 13C NMR(CDCl3, 75 MHz) δ 207.8, 172.3, 61.7, 54.7, 54.4, 54.0,44.3, 31.8, 25.2, 14.3. IR (cm−1): 3317, 2967, 1738, 1720,1292, 1209. HRMS (EI+) 199.1208 (calcd for C10H17NO3199.1208).2,2-Dimethyl-6-(4-vinylphenyl)piperidin-4-one (3n). 1HNMR (CDCl3, 300 MHz) δ 7.42-7.35 (m, 4H), 6.75-7.66(dd, J = 10.9, 17.6 Hz, 1H), 5.74 (d, J = 17.5 Hz, 1H), 5.24(d, J = 10.9 Hz, 1H), 4.21 (dd, J = 3.8, 11.0 Hz, 1H), 2.52-2.24 (m, 4H), 1.47 (bs, 1H), 1.32 (s, 3H), 1.20 (s, 3H); 13CNMR (CDCl3, 75 MHz) δ 209.6, 142.6, 137.3, 136.4, 126.9,126.6, 114.1, 55.8, 54.3, 54.0, 49.8, 32.3, 25.5. IR (cm−1):3307, 3006, 1711, 1652, 1293, 1276, 750. HRMS (EI+)229.1470 (calcd for C15H19NO 229.1467).2,2-Dimethyl-6-(pyridin-2-yl)piperidin-4-one (3o). 1HNMR (CDCl3, 300 MHz) δ 8.60-8.59 (m, 1H), 7.71-7.65 (m,1H), 7.29-7.20 (m, 2H), 4.32 (dd, J = 5.4, 9.4 Hz, 1H), 2.57-2.39 (m, 4H), 1.37 (s, 3H), 1.20 (s, 3H), 0.86 (bs, 1H); 13CNMR (CDCl3, 75 MHz) δ 209.9, 160.4, 149.8, 137.2, 123.0,122.0, 57.7, 55.0, 54.9, 48.6, 32.1, 25.6.2,2-Dimethyl-6-(thiophen-2-yl)piperidin-4-one (3p). 1HNMR (CDCl3, 300 MHz) δ 7.37-7.35 (m, 2H), 7.31-7.27 (m,1H), 4.19 (dd, J = 3.6, 11.2 Hz, 1H), 2.50-2.24 (m, 4H), 1.51(bs, 1H), 1.32 (s, 3H), 1.19 (s, 3H); 13C NMR (CDCl3, 75Synthesis of Piperidones  Bull. Korean Chem. Soc. 2014, Vol. 35, No. 12     3435MHz) δ 209.1, 141.6, 133.5, 128.9, 128.1, 55.5, 54.2, 54.0,49.8, 32.2, 25.5. IR (cm−1): 3306, 3101, 2963, 1712, 1475,1413, 1294, 1267, 829. HRMS (EI+) 209.0874 (calcd forC11H15NOS 209.0874).2,2-Dimethyl-6-(naphthalen-2-yl)piperidin-4-one (3q).1H NMR (CDCl3, 300 MHz) δ 7.84-7.81 (m, 4H), 7.56-7.45(m, 3H), 4.37 (dd, J = 4.0, 10.8 Hz, 1H), 2.61-2.28 (m, 4H),1.55 (bs, 1H), 1.35 (s, 3H), 1.24 (s, 3H); 13C NMR (CDCl3,75 MHz) δ 209.6, 140.4, 133.5, 133.1, 128.6, 127.9, 127.7,126.3, 126.0, 125.2, 125.0, 56.2, 54.3, 54.1, 49.8, 32.3, 25.6.6-(Benzo[d][1,3]dioxol-5-yl)-2,2-dimethylpiperidin-4-one (3r). 1H NMR (CDCl3, 300 MHz) δ 7.27-7.25 (m, 1H),6.96-6.86 (m, 1H), 6.78-6.75 (m, 1H), 5.94 (s, 2H), 4.12 (dd,J = 3.8, 10.9 Hz, 1H), 2.46-2.23 (m, 4H), 1.52 (bs, 1H), 1.31(s, 3H), 1.18 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 209.7,148.1, 147.2, 137.2, 120.0, 108.4, 107.2, 101.2, 56.0, 54.3,54.0, 50.1, 32.3, 25.6. IR (cm−1): 3309, 2964, 2901, 1711,1559, 1504, 1297, 1273, 1039, 932. HRMS (EI+) 247.1209(calcd for C14H17NO3 247.1208).Results and DiscussionTo find conditions suitable for the selective formation of4-piperidones, solvent and the amount of L-proline werevaried in the reaction of 1-(azidomethyl)-4-methoxybenzene(Table 1). In dioxane or THF the coupling reaction withacetone did not occur, although the N-H alimine was gene-rated (entries 1 and 2). The desired piperidone 3a wasformed only in 5% yield along with the aldol condensationproduct 6 in 9% yield when acetone was used as solvent(entry 3). Polar solvents such as DMF and DMSO wereeffective for the selective formation of 3a (entries 4 and 5).Increasing the amount of L-proline increased the yield andthe selectivity for 3a (entries 5-7). Decreasing the amount ofthe ruthenium catalyst 1 decreased the yield of 3a (entry 8).The substrate scope was explored (Table 2). A wide rangeof benzylic azides (2a-2i) were successfully transformed tothe expected 4-piperidones (3a-3i) in good to high yieldsexcept 1-(azidomethyl)-4-nitrobenzene (2j). The resultsimplicate that the transformation was not affected signifi-cantly by the substituents of benzene ring. The electron-withdrawing effect of nitro group would not be responsiblefor the poor result in the case of 3j, because the piperidonescontaining fluoride (3f) or cyano group (3i) were obtained ingood yield. Various functional groups are compatible withazido group to give potentially useful 4-piperidones. Parti-cularly, those (3k-3m) containing carbonyl groups are di-stinct examples, which cannot be provided by the previousmethod using excess ammonia. Alkenyl (3n) group was alsocompatible. The piperidones containing pyridyl (3o), thio-phenyl (3p) and naphthyl (3q) groups were obtained in 50-70% yield. Acetal group (3r) was also well tolerated in thistransformation. However, in contrast to the previous methodusing aldehyde and ammonia, it was not successful toproduce the derivatives containing aliphatic groups due tocomplex side reactions in our catalyst system. In fact, thepoor results are consistent with the well-known instability ofN-unsubstituted aliphatic aldimines.7 The attempts employ-ing other aldehydes or ketones such as 2-butanone, aceto-phenone and 1,3-dichloropropan-2-one instead of acetonewere not successful either.To our disappointment, the enantioselectivity for 3b wasonly 20 % ee in the reaction under the conditions of Table 2.Table 1. Synthesis of 2,2-dimethyl-6-substituted 4-piperidonesaEntrya Solvent L-proline 3a : 4 : 5 : 6 (%)b1 THF 35 mol % <1 : <1 : <1 : <12 Dioxane 35 mol % <1 : <1 : <1 : <13 Acetone 35 mol % 5 : <1 : <1 : 94 DMF 35 mol % 47 : 20 : <1 : 95 DMSO 35 mol % 56 : 23 : <1 : 116 DMSO 50 mol % 70 : 19 : <1 : 97 DMSO 100 mol % 80 : 14 : <1 : 68c DMSO 100 mol % 67 : 12 : <1 : 16aThe reaction was performed with 1 (2 mol %), 2a (0.25 mmol), L-proline, acetone (0.50 mL), and solvent (2.0 mL) at room temperaturefor 12 h under argon atmosphere with illumination of 30 W fluorescentlight. bDetermined by 1H NMR with cyclohexene as an internal standard.c1 mol % of 1 was used.Table 2. Substrate Scope of benzyl azidesa,baThe reaction was performed with azide (0.25 mmol), 1 (2.0 mol %), L-proline (100 mol %), acetone (0.50 mL), and DMSO (2.0 mL) at roomtemperature for 12 h under argon atmosphere with illumination of 30 Wfluorescent light. bIsolated yield3436     Bull. Korean Chem. Soc. 2014, Vol. 35, No. 12 Junghoon Han et al.We tried to improve the enantioselectivity with varyingreaction conditions (Table 3). Addition of water increasedthe enantioselectivity with decreasing the yield of 3b (entries2-4); with using 10 equivalents of water 3b was formed in58% yield and 44% ee (entry 3).8 The yield of 3b decreasedwith decreasing the amount of L-proline without improvingthe enantioselectivity (entries 5-7).According to the experimental outcomes and the previousreport describing the formation of oxazolidinone A fromproline and acetone,9 a plausible pathway for the formationof 4-piperidones is proposed in Scheme 3. First, N-unsub-stituted imines generated from the corresponding alkyl azidesby 1 under fluorescent light react with the enamine formedfrom acetone and proline to give β-aminoiminium inter-mediate B. The intermediate B undergoes imine conden-sation reaction with acetone to give C, which would betautomerized to another enamine D. Then 4-piperidones areproduced by the cyclization of D and the subsequent hydro-lysis of the cyclic intermediate E.ConclusionIn summary, we developed a new method for the synthesisof 2,2-dimethyl-6-substituted 4-piperidones with benzylazides and two equivalents of acetone under mild conditions.Our method extended the scope of accessible piperidones,including those having carbonyl groups which are notcompatible with the synthetic conditions using ammonia.Acknowledgments. This work was supported by the NationalResearch Foundation of Korea (No. 2012R1A2A1A01007235and No. 2008-0061892).References  1. For some recent examples, see: (a) Ranade, A. R.; Georg, G. I. J.Org. Chem. 2014, 79, 984. (b) Kim, Y. W.; Georg, G. I. Org. Lett.2014, 16, 1574. (c) Vu, H.-D.; Renault, J.; Toupet, L.; Uriac, P.;Gouault, N. Eur. J. Org. Chem. 2013, 6677. (d) Guo, F.; Dhakal,R. C.; Dieter, R. K. J. Org. Chem. 2013, 78, 8451. (e) Muller, D.;Alexakis, A. Org. Lett. 2012, 14, 1842. (f) Zhang, X.; Chen, J.;Han, F.; Cun, L.; Liao, J. Eur. J. Org. Chem. 2011, 1443. (g)Dieter, R. K.; Guo, F. J. Org. Chem. 2009, 74, 3843. (h) Clarke, P.A.; Zaytsev, A. V.; Morgan, T. W.; Whitwood, A. C.; Wilson, C.Org. Lett. 2008, 10, 2877. (i) Aznar, F.; Garcia, A.; Quinones, N.;Cabal, M. Synthesis 2008, 479. (j) Rosiak, A.; Hoenke, C.;Christoffers, J. Eur. J. Org. Chem. 2007, 4376. (k) Aznar, F.;Garcia, A.; Cabal, M. Adv. Synth. Cata. 2006, 348, 2443. (l)Focken, T.; Charette, A. B. Org. Lett. 2006, 8, 2985. (m) R. B. C.Jagt, J. G. deVries, B. L. Feringa, A. J. Minnaard, Org. Lett. 2005,7, 2433. (n) Shintani, R.; Tokunaga, N.; Doi , H.; Hayahsi, T. J.Am. Chem. Soc. 2004, 126, 6240.   2. Feng, L.; Xu, L.; Lam, K.; Zhou, Z.; Yip, C. W.; Chan, A. S. C.Tetrahedron Lett. 2005, 46, 8685.   3. Feng, L.-C.; Sun, Y.-W.; Tang, W.-J.; Xu, L.-J.; Lam, K.-L.; Zhou,Z.; Chan, A. S. C. Green Chem. 2010, 12, 949.  4. Lee, J. H.; Gupta, S.; Jeong, W.; Rhee, Y. H.; Park, J. Angew.Chem. Int. Ed. 2012, 51, 10851.  5. (a) Chen, G-M.; Brown, H. C. J. Am. Chem. Soc. 2000, 122, 4217.(b) Itsuno, S.; Watanabe, K.; Matsumoto, T.; Kuroda, S.; Yokoi,A.; El-Shehawy, A. J. Chem. Soc., Perkin Trans. 1 1999, 2011.  6. (a) Jeong, W.; Lee, J. H.; Lim, J.; Lee, W. J.; Seong, J.-H.; Park, J.;Rhee, Y. H. RSC Adv. 2014, 4, 20632.; (b) Han, J.; Jeon, M.; Pak,H.; Rhee, Y. H.; Park, J. Adv. Synth. Catal.; DOI 10.1002/adsc.adsc.201400584.  7. 7. Unlike the benzylic aldimines, N-unsubstituted aliphaticaldimine is unstable even at ambient conditions. It is enolizableand easily undergoes oligomerization itself.  8. 8. Some examples about the improvement of ee with H2O in L-proline catalysis reaction, see: (a) Enders, D.; Grondal, C.;Vrettou, M.; Synthesis 2006, 2155.; (b) Lu, M.; Zhu, D.; Lu, Y.;Hou, Y.; Tan, B.; Zhong, G.; Angew. Chem. Int. Ed. 2008, 47,10187.; (c) Zhu, D.; Lu, M.; Chua, P. J.; Tan, B.; Wang, F.; Yang,X.; Zhong, G.; Org. Lett. 2008, 10, 4585.; (d) Tan, B.; Zeng, X.;Lu, Y.; Chua, P. J.; Zhong, G. Org. Lett. 2009, 11, 1927.  9. 9. Schmid, M. B.; Zeitler, K.; Gschwind, R. M. Angew. Chem. Int.Ed. 2010, 49, 4997.Table 3. Enantioselectivity in the reaction of benzyl azide withacetone in the presence of L-prolinea,bEntrya L-proline H2O 3bb (ee)c : 4b : 5b1 100 mol % None 81 (20) : 16 : 32 100 mol % 5 equiv 57 (38) : 15 : 53 100 mol % 10 equiv 58 (44) : 16 : 74 100 mol % 15 equiv 57 (34) : 16 : 75 50 mol % None 72 (22) : 22 : 36 35 mol % None 60 (22) : 20 : 37 35 mol % 10 equiv 52 (32) : 12 : 23aThe reaction was performed with 1 (2 mol %), 2b (0.25 mmol), L-proline, acetone (0.50 mL), and DMSO (2.0 mL) at room temperaturefor 12 h under argon atmosphere with illumination of 30 W fluorescentlight. bDetermined by 1H NMR with cyclohexene as an internal standard.cDetermined by HPLC equipped with a chiral column (Chiral OD).Scheme 3. A plausible pathway for the formation 2,2-dimethyl-6-substitued 4-piperidones.

Synthesis of Piperidones from Benzyl Azides and Acetone

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Synthesis of Piperidones from Benzyl Azides and Acetone

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