Regioselective Functionalization of 2-Arylazetidines ...S1 Regioselective Functionalization of...
Transcript of Regioselective Functionalization of 2-Arylazetidines ...S1 Regioselective Functionalization of...
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Regioselective Functionalization of 2-Arylazetidines: Evaluating the ortho-Directing Ability of the Azetidinyl ring
and the α-Directing Ability of the N-Substituent Leonardo Degennaro,a,* Marina Zenzola,a Piera Trinchera,a Laura Carroccia,a Arianna Giovine,a Giuseppe
Romanazzi,b Aurelia Falcicchio,c and Renzo Luisia,*
aDepartment of Pharmacy – Drug Sciences, University of Bari “A. Moro”, Via E. Orabona 4, Bari 70125 – Italy; bDICATECh, Polytechnic of Bari, Via E. Orabona 4, Bari 70125 – Italy; cIstituto di Cristallografia
(IC-CNR), Via Amendola 122/o, 70125 Bari (Italy)
[email protected], [email protected]
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General
THF and Et2O was freshly distilled under a nitrogen atmosphere over Na/benzophenone. N,N,N',N'-tetramethylethylenediamine (TMEDA) was distilled over finely powdered CaH2, hexyllithium was purchased as hexane solution and was filtered on celite before using and title established by titration method.1 All the other chemicals were commercially available and used without further purification. Magnetic Resonance spectra were recorded using Varian 400 and 500 MHz, and Bruker 400, 500 and 600 MHz spectrometers. For the 1H, 13C and 11B NMR spectra (1H NMR 400, 500, 600 MHz, 13C NMR 100, 125, 150 MHz and 11B NMR 192 MHz), CDCl3, methanol-d4 and toluene-d8 were used as the solvents. MS-ESI analyses were performed on LC/MSD trap system VL. Melting points were uncorrected. GC-MS spectrometry analyses were carried out on a gas chromatograph (dimethylsilicon capillary column, 30 m, 0.25 mm i.d.) equipped with a mass selective detector operating at 70 eV (EI). Analytical thin layer chromatography (TLC) was carried out on precoated 0.25 mm thick plates of Kieselgel 60 F254; visualization was accomplished by UV light (254 nm) or by spraying a solution of 5 % (w/v) ammonium molybdate and 0.2 % (w/v) cerium(III) sulfate in 100 ml 17.6 % (w/v) aq. sulphuric acid and heating to 200 °C for some time until blue spots appear. Infra-red spectra of the compounds were recorded neat, as film, as KBr disc as indicated, by a Perkin-Elmer 283 spectrometer. For flash chromathography silica Gel 60, 0.04-0.063 mm particle size was used. CHN analyses were performed on a EuroEA 3000 analyzer. The high resolution mass spectrometry (HRMS) analyses were performed using a Bruker microTOF QII mass spectrometer equipped with an electrospray ion source (ESI) operated in positive ion mode. The sample solutions (CH3OH or CH3OH + 0.1%v/v HCOOH) were introduced by continuous infusion at a flow rate of 180 mL min‒1 with the aid of a syringe pump. The instrument was operated with end-plate offset and capillary voltages set to ‒500 V and ‒4500 V respectively. The nebulizer pressure was 0.4 bar (N2), and the drying gas (N2) flow rate was 4.0 L min‒1. The capillary exit and skimmer 1 voltages were 90 V and 30 V, respectively. The drying gas temperature was set at 180 °C. The calibration was carried out with sodium formate: a solution made up of 10 µl of 98% formic acid, 10 µl of sodium hydroxide (1.0 M), 490 µl of i-propanol and 490 µl of deionized water. The software used for the simulations was Bruker Daltonics DataAnalysis (version 4.0). All reactions involving air-sensitive reagents were performed under argon in oven-dried glassware using syringe septum cap technique. Optical rotation [α]D
20 values were measured by using a polarimeter with 1 dm cell path length; the concentration (c) is expressed in g/100mL. Enantiomeric ratios were determined by chiral HPLC, by chiral Gas Chromatography (GC), following the condition reported. 1 Suffert, J. J. Org. Chem. 1989, 54, 509-510.
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General procedure for synthesis of 1-methyl-2-arylazetidines
Method A
1-Methyl-2-arylazetidines were prepared as shown in Scheme 1, following a reported procedure.2 As an example, we report the synthesis of 1-metyl-2-phenylazetidine 3a.
+ Cl SO
ON C O
NH
O
ArEt2O
25 °C, 2 hAr N
O
ArMe N
Ar
MeKOH, TBAB, MeITHF, 8h
LiAlH4, AlCl3Et2O, 4 h, ∆
Scheme 1
N-Chlorosulfonyl isocyanate (36 mmol, 1.2 equiv.) was added dropwise to styrene (30 mmol, 1 equiv.) in dry diethyl ether (15 mL), at room temperature under an inhert atmosphere over 10 minutes. The mixture was stirred at room temperature for 2 h under a dry nitrogen atmosphere, and the solvent was removed under reduced pressure. The residue obtained was taken up in diethyl ether (20 mL) and added dropwise over 10 minutes to a vigorously stirred solution of water (20 mL), sodium carbonate (99 mmol, 3.3 equiv), sodium sulphite (45 mmol, 1.5 equiv), and ice (20 g). The solution was stirred for 1 h and filtered under vacuum. The organic layer was separated, and the acqueous layer was extracted with diethyl ether (5 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered and the solvent evaporated under vacuum to yield the pure product (90 %). The obtained 4-phenylazetidin-2-one (24 mmol, 1 equiv) was dissolved in anhydrous THF (120 mL) and tetrabutylammonium bromide (2.4 mmol, 0.1 equiv), KOH (26.4 mmol, 1.1 equiv) and CH3I (36 mmol, 1.5 equiv) were added and the solution was stirred at 25 °C for 8 h. The reaction mixture was filtered and the filtrate poured into water and extracted with Et2O. The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure to yield 1-methyl-4-phenylazetidin-2-one (70 %) that was employed, without further purification for the reduction reaction. To a solution of AlCl3 (50.4 mmol, 3 equiv) in dry diethyl ether (90 mL) was added carefully LiAlH4 (50.4 mmol, 3 equiv) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min, and subsequently refluxed for 30 min. 1-Methyl-4-phenylazetidin-2-one (16.8 mmol, 1 equiv) in diethyl ether (50 mL) was added slowly and after the addition was complete, reflux was maintained for 4 h. The reaction was cooled to room temperature and aqueous NaOH (20 % p/v) was added carefully. The aqueous phase was extracted with Et2O (3 x 50 mL), dried over Na2SO4 and evaporated under reduced pressure. Kughelrhor distillation (90°C, 1 x 10-2 torr) gave the 1-methyl-2-phenylazetidine as colorless oil (88 % yield).
2 a) Hemming, K.; Khan, M. N.; Kondakal, V. V. R.; Pitard, A.; Qamar, M. I.; Rice C. R. Org. Lett. 2012, 14, 126-129 ; b) Bergmann, H.-J.; Mayrhofer, R.; Otto, H.-H. Arch. Parm. 1986, 319, 203-216; c) Van Driessche, B.; Van Brabandt, W.; D’ hooghe, M.; Dejaegher, Y.; De Kimpe, N. Tetrahedron, 2006, 62, 6882-6892.
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Method B
The preparation of 1-metyl-2-phenylazetidine 3a is described (Scheme 2).
Scheme 2
To a solution of commercially available 3-chloro-1-phenylpropan-1-ol (10 mmol, 1 equiv) in CH2Cl2 (10 mL) at 25 °C, a solution of SOCl2 (30 mmol, 3 equiv) in CH2Cl2 (3 mL) was added dropwise. After 1 hour at 25 °C the reaction mixture was poured into water and aqueous NaOH (15% p/v) was slowly added to neutralise the excess of HCl. The aqueous phase was extracted with CH2Cl2 (3 x 15 mL) and the combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure to give 1-phenyl-1,3-dichloropropane that was employed without further purification. To a solution of 1-phenyl-1,3-dichloropropane in EtOH (12.5 mL) and Et3N (20 mmol, 2 equiv) at 25 °C, a solution of MeNH2 (33 % p/w in EtOH, 12.5 mL) was added. The reaction mixture was heated at 70 °C for 12 h and then allowed to cool to room temperature. The solvent was removed in vacuo and aqueous NaOH (15 % p/v) was added. The aqueous phase was extracted with CH2Cl2 (3x 20 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude mixture was purified to give the desired azetidine. This method was used for the synthesis of chiral azetidines (S)-3a and (S)-3e, commercially available (R)-3-chloro-1-phenylpropan-1-ol (er = 95:5) and 3-chloro-1-(4-chlorophenyl)propan-1-ol (er = 80:20) were used as starting materials. Absolute configuration to enantioenriched azetidine (S)-3a assigned assuming a retention in the reaction with SOCl2 and inversion in the cyclization step with MeNH2.
1-methyl-2-phenylazetidine 3a: Prepared following Method A. Colorless oil, 88%. 1H NMR (400 MHz, CDCl3) δ 2.12 (quint, J = 9.2, 1 H), 2.26 (dtd, J = 9.4, 7.3, 1.7 Hz, 1 H), 2.32 (s, 3 H), 2.84 (dt, J = 9.7, 7.0 Hz, 1 H), 3.41-3.46 (m, 1 H), 3.85 (t, J = 8.2 Hz, 1 H), 7.20-7.26 (m, 1 H), 7.32 (t, J = 7.6 Hz, 2 H), 7.36
(d, J = 7.1 Hz, 2 H). 13C NMR (150 MHz, toluene-d8) δ 28.0, 44.2, 53.0, 71.4, 126.9, 127.3, 128.5, 144.0. GC-MS (70 eV) m/z (%) 147 [M+, 12], 146 [M-H+, 37], 119 (22), 118 (100), 104 (46). FT-IR (film, cm-1) υ 2959, 2934, 2826, 1452, 1190, 964, 745, 699. HRMS (ESI-TOF) m/z [M+Na]+ calcd for C10H13NNa 170.0940; found 170.0938. (2S)-1-methyl-2-phenylazetidine (S)-3a: [α]D
20 = − 117 (c = 0.55, CHCl3). The enantiomeric ratio (er = 90:10) was determined by chiral GC (Cycloβdex, iso 90°C, length 30mt, i.d. 0.25). For enantioenriched resulted t1 = 23.47 min (Area% 90,36), t2 = 24.12 min (Area% 9.64).
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1-methyl-2-(naphthalen-1-yl)azetidine 3b: Prepared following Method B. Orange oil, 72%. 1H NMR (400 MHz, CDCl3) δ 2.09 (quint, J = 9.3 Hz, 1 H), 2.45 (s, 3 H), 2.59 (dt, J = 7.9, 5.9 Hz, 1 H), 3.05 (dt, J = 9.5, 7.0 Hz, 1 H), 2.51-2.55 (m, 1 H), 4.58 (t like, J = 8.1 Hz, 1 H), 7.43-7.50 (m, 3 H), 7.72 (d, J
= 8.2 Hz, 1 H), 7.75 (dd, J = 7.1, 1.1 Hz, 1 H), 7.82.-7.88 (m, 2 H). 13C NMR (100 MHz, CDCl3) δ 28.0, 45.0, 53.5, 68.4, 122.6, 123.1, 125.5, 125.8, 126.0, 127.0, 128.9, 130.4, 133.8, 139.2. FT-IR (film, cm-1) υ 2930, 2827, 2770, 1509, 1443, 1328, 1190, 1141, 978, 955, 801, 776. HRMS (ESI-TOF) m/z [M+Na]+ calcd for C14H15NNa 220.1097; found 220.1097.
2-(4-methoxyphenyl)-1-methylazetidine 3c: Prepared following Method B. Yellow oil, 55%. 1H NMR (400 MHz, CDCl3) δ 1.97-2.06 (m, 1 H), 2.09-2.16 (m, 1 H), 2.20 (s, 3 H), 2.71 (td, J = 6.8, 9.6 Hz, 1H), 3.30-3.34 (m, 1 H), 3.64-3.71 (m overlapping s at 3.69, 1 H), 3.69 (s, 3 H), 6.75-6.79
(m, 2 H), 7.19-7.23 (m, 2 H). 13C NMR (100 MHz, CDCl3) δ 27.2, 44.4, 52.9, 55.4, 71.0, 113.8, 128.0, 135.2, 159.1. FT-IR (film, cm-1) υ 2956, 2830, 1611, 1512, 1247, 1171, 1037, 833. HRMS (ESI-TOF) m/z [M+H]+ calcd for C11H16NO 178.1226; found 178.1224.
General procedure for lithiation-electrophile trapping sequence of azetidines 3:
To a stirred solution of azetidine (0.5 mmol, 1 equiv) and TMEDA (0.65 mmol, 1.3 equiv) in Et2O (4 mL) at 25 °C a solution of hexyllithium (2.3 M in hexane, 0.65 mmol, 1.3 equiv.) was added dropwise. After 1 hour at 25 °C the electrophile (0.65 mmol, 1.3 equiv) neat if liquid and in 1.0 ml of solvent if solid was added to the resulting deep orange solution. After the reaction was complete, as determined by GC or TLC, the reaction mixture was poured in saturated aqueous NH4Cl (10 mL) and extracted with Et2O (3 x 10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Chromatography on silica gel (Hexane/AcOEt 3/7 or CH2Cl2/MeOH) afforded the ortho-substituted azetidines 4 (or 7).
1-methyl-2-(o-tolyl)azetidine 4a: Column chromatography on silica gel (CH2Cl2/MeOH 90:10), colorless oil, 95%. 1H NMR (400 MHz, CDCl3) δ 1.94 (quint, J = 9.2 Hz, 1 H), 2.21 (s, 3 H), 2.32-2.43 (m overlapping s at 2.36 ppm, 1 H), 2.36 (s, 3 H), 2.89-2.95 (m, 1 H), 3.37-3.54 (m, 1 H), 4.06 (t like, J = 7.6,
1 H), 7.08-7.15 (m, 2 H), 7.23 (t, J = 7.8 Hz, 1 H), 7.59 (d, J = 7.6 Hz, 1 H). 13C NMR (100 MHz, CDCl3) δ 18.8, 26.7, 44.8, 53.2, 68.5, 125.4, 126.2, 126.6, 129.9, 134.5, 141.4. GC-MS (70 eV) m/z (%) 161 [M+], 132 (51), 118 (100), 117 (80), 115 (22), 91 (20), 44 (36). FT-IR (film, cm-1) υ 2958, 2930, 2827, 2771, 1458, 1446, 1351, 1192, 967, 748. HRMS (ESI-TOF) m/z [M+Na]+ calcd for C11H15NNa 184.1097; found 184.1087.
NMe
Me
NMe
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1-methyl-2-(2-methylnaphthalen-1-yl)azetidine 4b: Column chromatography on silica gel (Hexane/AcOEt 50:50), yellow oil, 96%. 1H NMR (600 MHz, CDCl3) δ 2.34-2.36 (m overlapping s at 2.36 ppm, 1 H), 2.36 (s, 3 H), 2.61-2.66 (m overlapping s at 2.66 ppm, 1 H), 2.66 (s, 3 H),
2.91-3.00 (m, 1 H), 3.66-3.74 (m, 1 H), 4.77 (t like, J = 7.8 Hz, 1 H), 7.26 (d, J = 8.3 Hz, 1 H), 7.42 (t, J = 7.6 Hz, 1 H), 7.51 (t, J = 7.4 Hz, 1 H), 7.66 (d, J = 7.9 Hz, 1 H), 7.80 (d, J = 7.4 Hz, 1 H), 9.43 (d, J = 8.2 Hz, 1 H). 13C NMR (150 MHz, CDCl3) δ 21.1, 25.6, 45.8, 53.2, 69.2, 124.6, 125.3, 125.8, 127.7, 128.6, 129.7, 133.1, 133.36, 133.38, 134.0. FT-IR (film, cm-1) υ 3049, 2859, 2829, 2823, 1448, 1194, 952, 811, 742. HRMS (ESI-TOF) m/z [M+H]+ calcd for C15H18N 212.1434; found 212.1435.
2-(4-methoxy-2-methylphenyl)-1-methylazetidine 4c: Column chromatography on silica gel (Hexane/AcOEt 30:70). Yellow oil. 86%. 1H NMR (400 MHz, CDCl3) δ 1.78-2.00 (m, 1 H), 2.19 (s, 3H), 2.28-2.35 (m, overlapping s at 2.33, 1 H), 2.33 (s, 3 H), 2.86-2.90 (m, 1 H), 3.40-3.44 (m,
1H), 3.76 (s, 3 H), 3.98 (t, J = 8.0 Hz, 1 H), 6.65 (d, J = 2.5 Hz, 1 H), 6.75 (dd, J = 2.5, 8.3 Hz, 1 H), 7.49 (d, J = 8.3 Hz, 1 H). 13C NMR (150 MHz, CDCl3) δ 18.9, 26.7, 44.4, 52.9, 55.1, 67.9, 110.8, 115.8, 126.7, 133.3, 135.9, 158.3. GC-MS (70 eV) m/z (%) 191 [M+, 13], 176 (6), 162 (15), 148 (100), 133 (9), 117 (10), 105 (22), 77 (11), 42 (5). FT-IR (film, cm-1) υ 2955, 2771, 1609, 1500, 1452, 1253, 1051, 968, 844. ESI-MS m/z : [M+H]+ 191. HRMS (ESI-TOF) m/z [M+Na]+ calcd for C12H17NONa 214.1202; found 214.1201.
2-(2-chlorophenyl)-1-methylazetidine 4d: Column chromatography on silica gel (Hexane/AcOEt 30:70), yellow oil, 93%. 1H NMR (400 MHz, CDCl3) δ 1.93 (quint, J = 9.2 Hz, 1 H), 2.34 (s, 3 H), 2.47 (dtd, J = 9.7, 7.6, 2.0 Hz, 1 H), 2.92 (ddd, J = 9.6, 7.5, 6.6 Hz, 1 H), 3.41-3.45 (m, 1 H), 4.20 (t like, J = 8.1 Hz, 1 H),
7.17 (t, J= 7.5 Hz, 1 H), 7.29-7.21 (m, 2 H), 7.64 (d, J = 7.5 Hz, 1 H). 13C NMR (100 MHz, CDCl3) δ 26.6, 44.7, 53.1, 68.0, 127.0, 127.4, 127.9, 129.1, 132.1, 140.9. GC-MS (70 eV) m/z (%) 183 [M+2+, 4], 181 [M+, 11], 154 (33), 152 (100), 146 (5), 140 (10), 138 (31), 103 (23). FT-IR (film, cm-1) υ 2961, 2932, 2930, 2774, 1468, 1440, 1350, 1188, 1054, 1031, 970, 753. HRMS (ESI-TOF) m/z [M+H]+ calcd for C10H13ClN 182.0731; found 182.0728.
2-(2-bromophenyl)-1-methylazetidine 4e: Column chromatography on silica gel (Hexane/AcOEt 30:70), colorless oil, 55%. 1H NMR (600 MHz, CDCl3) δ 1.93 (quint, J = 9.3 Hz, 1 H), 2.38 (s, 3 H), 2.55 (dtd, J = 9.7, 7.6, 2.0 Hz, 1 H), 2.95-2.99 (m, 1 H), 3.45-3.47 (m, 1 H), 4.19 (t like, J = 8.1 Hz, 1 H), 7.10 (td, J 7.8,
1.6 Hz, 1 H), 7.34 (t, J = 7.6 Hz, 1 H), 7.49 (dd, J = 7.9, 0.8 Hz, 1 H), 7.68 (dd, J = 7.7, 1.3 Hz, 1 H). 13C NMR (150 MHz, CDCl3) δ 26.7, 44.6, 52.9, 70.2, 122.0, 127.7, 127.9, 128.4, 132.5, 142.4. GC-MS (70 eV) m/z (%) 227 [M+2+, 12], 225 [M+, 12], 198 (99), 196 (100), 184 (30), 182 (30), 103 (44), 42 (29). FT-IR (film, cm-1) υ 2958, 2931, 2829, 1465, 1437, 1346, 1188, 1021, 971, 752. HRMS (ESI-TOF) m/z [M+H]+ calcd for C10H13BrN 226.0226; found 226.0213.
NMe
Me
NMe
Cl
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1-methyl-2-[2-(methyldiphenylsilyl)phenyl]azetidine 4f: Column chromatography on silica gel (Hexane/AcOEt 30:70), pale yellow oil, 85%. 1H NMR (400 MHz, CDCl3) δ 0.86 (s, 3 H), 1.53-1.59 (m, 1 H), 1.72-1.78 (m, 1 H), 1.90 (s, 3 H), 2.49 (dt, J = 9.7, 7.2 Hz, 1 H), 3.25 (t like, J = 6.6 Hz, 1 H), 3.91 (t like, J = 7.9 Hz, 1 H), 7.18 (td, J = 7.4, 1.3 Hz, 1 H), 7.27-7.39 (m, 7 H), 7.45-
7.49 (m, 4 H), 7.59 (dd, J = 7.8, 1.7 Hz, 1 H), 7.95 (d, J = 7.7 Hz, 1 H). 13C NMR (150 MHz, CD3OD) δ -1.1, 29.7, 43.9, 53.2, 72.6, 128.1, 128.7, 128.8, 129.11, 129.12, 130.6, 131.6, 135.0, 135.5, 136.28, 136.30, 137.4, 137.95, 138.0, 139.2. GC-MS (70 eV) m/z (%) 342 [M-1+, 3], 314 (20), 300 (55), 265 (28), 264 (25), 250 (93), 238 (27), 208 (25), 207 (100), 181 (20), 105 (27). FT-IR (film, cm-1) υ 2957, 2920, 2850, 1428, 1258, 1110, 1075, 791, 722, 700. HRMS (ESI-TOF) m/z [M+Na]+ calcd for C23H25NSiNa 366.1648; found 366.1639.
2-[2-(1-methylazetidin-2-yl)phenyl]propan-2-ol 4g: Column chromatography on silica gel (CH2Cl2/MeOH 90:10), colorless oil, 60%. 1H NMR (600 MHz, CD3OD) δ 1.60 (s, 3 H), 1.63 (s, 3H), 2.02-2.09 (m, 1 H), 2.31 (s, 3 H), 2.37-2.41 (m, 1 H), 2.90-2.94 (m, 1 H), 3.42-3.44 (m, 1 H), 4.98-5.01 (m, 1 H), 7.18 (td, J = 7.8, 1.5 Hz, 1 H), 7.27 (td, J = 7.9, 1.1 Hz, 1 H), 7.37 (dd, J = 7.9, 1.1
Hz, 1 H), 7.87 (dd, J = 7.8, 1.2 Hz, 1 H). 13C NMR (150 MHz, CD3OD) δ 30.4, 32.2, 32.7, 44.5, 53.4, 70.1, 73.9, 126.3, 127.9, 128.1, 130.2, 141.5, 147.3. GC-MS (70 eV) m/z (%) 205 [M+, 10] , 204 [M-H+, 22], 190 (28), 174 (33), 162 (44), 159 (76), 158 (43), 147 (69), 146 (52), 145 (34), 131 (35), 129 (71), 128 (36), 44 (100). FT-IR (film, cm-1) υ 3378, 2970, 2930, 2825, 2770, 1474, 1444, 1378, 1360, 1243, 1225, 1172, 1141, 959, 763, 746. HRMS (ESI-TOF) m/z [M+H]+ calcd for C13H20NO 206.1539; found 206.1545.
[2-(1-methylazetidin-2-yl)phenyl]diphenylmethanol 4h: crystallization from MeOH, white solid, mp 163 °C, 90%. 1H NMR (400 MHz, CDCl3) δ 1.77 (s, 3 H), 1.92-2.03 (m, 2 H), 2.72 (dt, J = 9.4, 7.8 Hz, 1 H), 3.31 (t like, J = 6.5 Hz, 1 H), 4.12 (t, J = 8.7 Hz, 1 H), 6.66 (d, J = 7.9 Hz, 1 H), 7.03 (t, J = 7.6 Hz, 1 H), 7.17-7.33 (m, 12 H), 9.60 (bs, 1 H). 13C NMR (150 MHz, CD3OD) δ 29.6, 44.1,
53.2, 70.4, 83.7, 127.0, 127.96, 127.98, 128.7, 128.9 129.1, 129.3, 130.5, 130.6, 143.5, 146.6, 149.2, 149.5. ESI-MS m/z (int. rel.): 330 [M+1]+ (100). FT-IR (KBr, cm-1) υ 3225, 2957, 2939, 2838, 1445, 1370, 1166, 1023, 751, 700. HRMS (ESI-TOF) m/z [M+H]+ calcd for C23H24NO 330.1852; found 330.1846. (S)-(2-(1-methylazetidin-2-yl)phenyl)diphenylmethanol (S)-4h: [α]D
20 = −70 (c 0.55, CHCl3). The enantiomeric ratio (er = 95:5) was determined by chiral HPLC (Cellulose – Lux1, Hexane – iPrOH 99:1, 0.5% Et2NH, 0.5 mL/min, 254 nm). For racemic t1 = 15.54 min, t2 = 16.31 min; for enantioenriched resulted t1 = 15.44 min (Area% 95.44), t2 = 16.10 min (Area% 4.56).
[5-methoxy-2-(1-methylazetidin-2-yl)phenyl]diphenylmethanol 4i: White solid, mp 138 °C (methanol), 96%. 1H NMR (600 MHz, CD3OD) δ 1.80-1.88 (m overlapping s at 1.88, 2 H), 1.88 (s, 3 H), 2.63 (q like J = 7.8 Hz, 1 H), 3.28 (dt, J = 2.4, 7.4 Hz, 1 H), 3.61 (s, 3 H), 4.51 (t, J = 8.2 Hz, 1
H), 6.21 (d, J = 2.6 Hz, 1 H), 6.91 (dd, J = 2.6, 8.5 Hz,1 H), 7.20-7.22 (m, 2 H), 7.23-7.32 (m, 8 H), 7.72 (d, J = 8.5 Hz, 1 H). 13C NMR (150 MHz, CD3OD) δ 28.0, 42.3, 51.6, 54.0, 68.7, 82.2, 111.5,
NMe
OH
MeMe
Si
NMe
Ph Ph
Me
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116.4, 126.66, 126.69, 127.36, 127.38, 127.7, 127.9, 130.7, 133.3, 146.8, 147.6, 147.8, 157.8. FT-IR (KBr, cm-1) υ 3351, 2955, 2834, 1606, 1573, 1488, 1445, 1293, 1242, 1038, 760, 701.
2-(2-chloro-4-methoxyphenyl)-1-methylazetidine 4j: Yellow oil, 96%. 1H NMR (300 MHz, CDCl3) δ 1.87-1.99 (m, 1 H), 2.35 (s, 3 H), 2.38-2.47 (m, 1 H), 2.92 (ddd, J = 9.6, 7.5, 6.5 Hz, 1 H), 3.41-3.47 (m, 1 H), 3.78 (s, 3 H), 4.19 (t, J = 8.0 Hz, 1 H), 6.84 (dd, J = 2.5, 8.3, 1 H), 6.87 (d, J = 2.5, 1
H), 7.56 (d, J = 8.3 Hz, 1 H). 13C NMR (75 MHz, CDCl3) δ 26.9, 44.7, 53.2, 55.8, 67.6, 113.0, 114.8, 128.4, 132.7, 132.9, 159.2. FT-IR (film, cm-1) υ 2933, 2832, 1607, 1570, 1494, 1250, 1045, 866.
5-methoxy-2-(1-methylazetidin-2-yl)-N-(p-tolyl)benzamide 4k: While solid, mp 112°C, 90%. 1H NMR (600 MHz, CDCl3) δ 2.27-2.31 (m, 1 H), 2.35 (s, 3 H), 2.45 (s, 3 H), 2.51-2.54 (m, 1 H), 2.93-3.00 (m, 1 H), 3.45-3.52 (m, 1 H), 3.86 (s, 3 H), 4.16-4.24 (m, 1 H), 6.92 (dd, J = 2.7, 8.3 Hz, 1 H), 7.19 (d, J = 8.1 Hz, 2 H), 7.27-7.33
(m, 1 H), 7.5 (d, J = 2.4 Hz, 1 H), 7.65 (d, J = 8.3 Hz, 2 H). 13C NMR (150 MHz, CDCl3) δ 20.9, 25.9, 43.2, 52.2, 55.5, 72.1, 115.9, 116.2, 119.7, 129.5, 132.4, 133.5, 136.8, 138.8, 159.6, 167.1. FT-IR (KBr, cm-1) υ 3433, 2933, 2852, 2771, 1664, 1606, 1513, 1329, 1279, 1040, 833, 819, 773, 516.
[1-(1-methylazetidin-2-yl)naphthalen-2-yl]diphenylmethanol 4l: Column chromatography on silica gel (Hexane/AcOEt 50:50) white solid, mp 189 °C, 74%. 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 3 H), 2.65-2.79 (m, 2 H), 2.96-3.02 (m, 1 H), 3.63 (t like, J = 6.5 Hz, 1 H), 5.01 (t like, J = 8.9 Hz, 1 H), 6.90 (d, J = 8.8 Hz, 1 H), 7.13 (d, J = 6.7 Hz, 2 H), 7.18-7.27 (m, 6 H), 7.36
(d, J = 7.3 Hz, 2 H), 7.43-7.52 (m, 3 H), 7.76 (d, J = 7.8 Hz, 1 H), 8.02 (d, J = 8.3 Hz, 1 H). 13C NMR (100 MHz, CDCl3) δ 28.2, 43.8, 52.9, 69.9, 83.8, 123.7, 125.5, 125.6, 126.4, 126.7, 126.8, 127.8, 128.7, 128.9, 131.0, 132.3, 132.4, 134.7, 144.2, 149.8, 151.2. FT-IR (KBr, cm-1) υ 3437, 2955, 2851, 2773, 1483, 1442, 1175, 1049, 823, 761, 747, 703. HRMS (ESI-TOF) m/z [M+H]+ calcd for C27H26NO 380.2009; found 380.2007.
NMe
OH
Ph Ph
NMe
MeOO
HN
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General procedure for lithiation/borylation sequence of azetidines 3:
To a stirred solution of azetidine (0.5 mmol, 1 equiv.) and TMEDA (0.65 mmol, 1.3 equiv.) in Et2O (4 mL) at 25 °C a solution of hexyllithium (2.3 M in hexane, 0.65 mmol, 1.3 equiv.) was added dropwise. After 1 hour at 25 °C the 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.65 mmol, 1.3 equiv.) was added to the resulting orange solution. After 1 hour, the reaction mixture was poured in saturated aqueous NH4Cl (10 mL) and extracted with Et2O (3 x 10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Chromatography on silica gel afforded the azetidines-boronate.
1-methyl-2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]azetidine 6a: Column chromatography on silica gel (AcOEt), white solid, mp 141 °C, 75%. 1H NMR (400 MHz, CDCl3) δ 1.19 (s, 6 H), 1.21 (s, 6 H), 1.97-2.07 (m, 1 H), 2.50-2.58 (m overlapping s at 2.56 ppm, 1 H), 2.56 (s, 3 H), 3.25 (q like, J = 9.0 Hz, 1 H), 4.20 (td, J = 9.0, 4.5 Hz, 1 H), 4.57 (t like, J = 8.3 Hz, 1 H), 6.87 (d, J = 7.5 Hz, 1 H), 7.11 (td, J = 7.4, 1.3 Hz, 1 H), 7.17 (td, J
= 7.2, 1.0 Hz, 1 H), 7.54 (d, J = 7.2 Hz, 1 H). 13C NMR (100 MHz, CDCl3) δ 24.3, 26.1, 26.4, 45.6, 51.8, 74.1, 80.3, 121.3, 127.85, 127.9, 131.9, 144.1. 11B NMR (192 MHz, CDCl3) δ 13.4 (bs). GC-MS (70 eV) m/z (%) 273 [M+, 31], 272 [M-H+, 40], 258 (53), 244 (87), 215 (55), 214 (41), 187 (100), 186 (40), 173 (25), 172 (44), 170 (23), 162 (58), 158 (20), 157 (27), 146 (49), 145 (93), 131 (34), 130 (48), 129 (35), 117 (24), 114 (25), 105 (22), 42 (22). FT-IR (KBr, cm-1) υ 2981, 2928, 1358, 1260, 1215, 1197, 1183, 1158, 1103, 1040, 1019, 759. HRMS (ESI-TOF) m/z [M+Na]+ calcd for C16H24BNO2Na 296.1795; found 296.1779.
1-methyl-2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl]azetidine 6b: Column chromatography on silica gel (Hexane/AcOEt 30:70), white solid, mp 160 °C. 1H NMR (400 MHz, CDCl3) δ 1.18 (s, 3 H), 1.21 (s, 3 H), 1.34 (s, 3 H), 1.42 (s, 3 H), 2.08-2.18 (m, 1 H), 2.73 (s, 3 H), 2.77-2.85 (m, 1 H), 3.39-3.45 (m, 1 H), 4.41 (td, J = 9.4, 5.1 Hz, 1 H), 5.11 (t like, J = 8.1 Hz, 1 H), 7.36-7.42 (m, 3 H), 7.69 (d, J= 8.1 Hz, 1 H), 7.73 (d, J= 8.1 Hz, 1 H),
7.81-7.84 (m, 1 H). 13C NMR (100 MHz, CDCl3) δ 23.2, 25.9, 26.25, 26.3, 26.9, 46.0, 52.4, 73.0, 80.1, 80.5, 122.2, 125.2, 125.5, 127.9, 128.0, 128.8, 129.1, 134.0, 139.8. 11B NMR (192 MHz, CDCl3) δ 8.2 (bs). FT-IR (KBr, cm-1) υ 2983, 2966, 2925, 1447, 1382, 1359, 1303, 1275, 1228, 1180, 1155, 1092, 1050, 968, 880, 827, 753, 693. HRMS (ESI-TOF) m/z [M+H]+ calcd for C15H18N 212.1434; found 212.1435.
N Me
BO
O
NMe
BO
O
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2-(2-chloro-6-methylphenyl)-1-methylazetidine 7a: Column chromatography on silica gel (AcOEt). Yellow oil, 96%. 1H NMR (600 MHz, CD3OD) δ 2.23-2.26 (m overlapping s at 2.26 ppm, 1 H), 2.26 (s, 3 H), 2.47-2.53 (m, 1 H), 2.72 (s, 3 H), 2.85-2.89 (m, 1 H), 3.49 (t like, J = 7.4 Hz, 1 H), 4.75 (t like, J = 8.7 Hz, 1 H), 7.05-7.07 (m , 2 H), 7.15-7.17 (m, 1 H). 13C NMR
(150 MHz, CDCl3) δ 20.6, 23.8, 45.6, 52.9, 68.6, 127.6, 127.8, 130.7, 134.6, 136.0, 140.6. FT-IR (film, cm-1) υ 2929, 2827, 1453, 772. HRMS (ESI-TOF) m/z [M+Na]+ calcd for C11H14ClNNa 218.0707; found 218.0702.
[3-chloro-2-(1-methylazetidin-2-yl)phenyl]diphenylmethanol 7b: Column chromatography on silica gel (Hexane/AcOEt 90:10), white solid, mp 115 °C, 85%. 1H NMR (400 MHz, CDCl3) δ 1.42 (s, 3 H), 2.28 (q, J = 9.6 Hz, 1 H), 2.47-2.54 (m, 1 H), 2.81-2.88 (m, 1 H), 3.46-3.50 (m, 1 H), 4.71 (t like, J = 8.8 Hz, 1 H), 6.59 (d, J = 8.0 Hz, 1 H), 6.91 (t, J = 7.9 Hz, 1 H), 7.10-7.13 (m, 2 H), 7.19-
7.27 (m, 9 H). 13C NMR (100 MHz, CDCl3) δ 25.9, 43.8, 52.6, 69.7, 83.4, 126.1, 126.7, 126.9, 127.0, 127.66, 127.7, 127.9, 128.5, 128.6, 128.63, 128.9, 131.4, 134.9, 137.8, 148.6, 149.5, 150.4. FT-IR (KBr, cm-1) υ 3369, 2853, 1487, 1445, 1179, 1046, 733, 701. HRMS (ESI-TOF) m/z [M+H]+ calcd for C23H22ClNO 364.1463; found 364.1467.
Synthesis of 2-(3,3-diphenyl-1,3-dihydroisobenzofuran-1-yl)-N-methylethanamine:
A a solution of orthohydroxyalkylated phenylazetidine (1.0 mmol) in 3 mL glacial acetic acid was heated at 90 °C and the resulting mixture stirred until the substrate disappeared as determined by TLC. The reaction mixture allowed to cool to room temperature and 10 mL of aqueous NaOH (20 % p/v) was added to neutralize the excess of acid. The aqueous phase was extracted with Et2O (3 × 10 mL), dried over Na2SO4, and evaporated under reduced pressure. Crystallization from CH3OH give the pure product.
2-(3,3-diphenyl-1,3-dihydroisobenzofuran-1-yl)-N-methylethanamine 8: white solid, mp 102 °C, 70%. 1H NMR (600 MHz, CDCl3) δ 2.08 (td, J = 14.0, 7.5 Hz, 1 H), 2.31-2.37 (m overlapping s at 2.34 ppm, 1 H), 2.34 (s, 3 H), 2.84-2.88 (m, 1 H), 2.95 (ddd, J = 12.2, 7.5, 6.4 Hz, 1 H), 4.67 (bs, 1 H), 5.36 (dd, J = 7.5, 3.4, 1 H), 7.18-7.35 (m, 14 H). 13C NMR (150 MHz, CDCl3) δ 33.5, 34.5, 47.5, 80.9, 92.7, 121.3, 124.2, 127.1, 127.5, 127.7, 127.8, 127.9, 128.2, 128.3, 141.6, 144.2, 144.6, 145.5. FT-IR (KBr, cm-1) υ 3585, 3025, 2925, 2850, 1577,
1490, 1446, 1400, 1330, 1240, 1157, 1111, 1052, 997, 920, 756, 699. HRMS (ESI-TOF) m/z [M+H]+ calcd for C23H24NO 330.1852; found 330.1840. (2R)-2-(3,3-diphenyl-1,3-dihydroisobenzofuran-1-yl)-N-methylethanamine (R)-8: [α]D
20 = +11.4 (c 0.35, CHCl3 ). The enantiomeric ratio (er = 98:2) was determined by chiral HPLC (Cellulose – Lux1, Hexane – iPrOH 90:10, 0.3% Et2NH, 1.0 mL/min, 254 nm). For racemic t1 =
Cl
Me
NMe
NMe
Cl
Ph Ph
OH
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6.76 min, t2 = 7.91 min; for enantioenriched resulted t1 = 6.79 min (Area% 97.38), t2 = 7.71 min (Area% 2.62).
Preparation of N-Boc azetidine 9
To 0.5 g (3.4 mmol) of 4-phenyl-2-azetidinone in 5 mL anhydrous Et2O under nitrogen at 0 °C lithium aluminum hydride was added portion-wise (259 mg, 6.8 mmol), and the mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature, 20% aqueous sodium hydroxide (10 mL) was added and the mixture was filtered. The filtrate was extracted with dichloromethane (3 × 10 mL) and the combined organic layers were dried over Na2SO4. After filtration and evaporation of the solvent the product was used in the next step without further purification. Di-tert-butyl dicarbonate (763 mg, 3.5 mmol) was added to a mixture of the azetidine (452 mg, 3.4 mmol) and Et3N (1.34 mL, 10.2 mmol) in CH2Cl2 (40 ml) and the mixture was stirred for 16 h. The water was added to the mixture and after extraction with Et2O, anhydrification over Na2SO4, evaporation of the solvent and purification by column chromatography on silica gel (hexane/EtOAc 9:1) 657 mg (83% yield) of N-tert-butoxycarbonyl-2-phenylazetidine 9 was isolated as colorless oil.
1-tert-Butoxycarbonyl-2-phenylazetidine 9: 1H NMR (600 MHz, CDCl3) δ 1.32 (bs, 9 H), 2.11-2.16 (m, 1 H), 2.59-2.65 (m, 1 H), 3.99 (t like, J = 7.6 Hz, 2 H), 5.18 (t like, J = 7.0 Hz, 1 H), 7.24-7.35 (m, 5 H). 13C NMR (150 MHz, CDCl3) δ 25.6, 28.2, 46.4, 65.6, 79.4, 125.8, 127.2, 128.3, 142.5, 156.5. FT-IR (film, cm-1) υ 2974, 1701, 1389, 1364, 1132, 698.
General procedure for the lithiation/trapping sequence on N-Boc azetidine 9.
To a stirred solution of N-Boc-azetidine (0.5 mmol, 1 equiv) and the electrophile (0.55 mmol, 1.1 equiv) in 2-MeTHF (4 mL) at -84 °C, a solution of hexyllithium (2.3 M in hexane, 0.65 mmol, 1.3 equiv.) was added dropwise. After the reaction was complete, as determined by GC or TLC, the reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) and extracted with Et2O (3 x 10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Chromatography on silica gel afforded the α-substituted azetidines 10.
1-tert-Butyl-2-(hydroxydiphenylmethyl)-2-phenylazetidine-1-carboxylate 10a: 1H NMR (600 MHz, CD3OD, mixture of rotamers ca 90:10 ratio) δ 1.42 (s, 9 H), 2.62-2.67 (m,1 H), 3.05-3.09 (m, 1 H), 3.17-3.21 (m, 1 H), 3.83-3.87 (m, 1 H), 7.11-7.17 (m, 3 H), 7.23-7.33 (m, 9 H), 7.41-7.43 (m, 1 H), 7.48-7.51 (m, 2 H). 13C NMR (150 MHz, CD3OD, selected data) δ 27.3, 29.3, 30.6, 45.4, 79.8, 80.7, 82.3, 126.7, 126.9, 127.2, 127.4, 127.9, 128.1, 129.0, 129.6, 132.4, 142.5, 146.1, 156.5.
HRMS (ESI-TOF) m/z [M+Na]+ calcd for C27H29NO3Na 438.2040; found 438.2025.
1-tert-Butyl-2-(methyldiphenylsilyl)-2-phenylazetidine-1-carboxylate 10b: 1H NMR (600 MHz, CD3OD, mixture of rotamers ca 50:50 ratio) δ 0.60 and 0.66 (2 x s, 3 H), 1.16 and 1.32 (2 x s, 9 H), 2.19-2.30 (2 x m, 1 H), 3.05-3.14 (2 x m, 1 H), 3.71-3.76 and 3.88-3.92 (2 x m, 1 H), 7.13-7.38 (2 x m, 12 H), 7.48-7.50 (2 x m, 2 H), 7.71 (2 x d like, J = 6.6 Hz, 1 H). 13C NMR (150 MHz, CD3OD, selected data)
δ -6.2, -5.6, 27.1, 27.3, 28.4, 29.0, 45.8, 66.9, 67.9, 78.8, 80.8, 125.4, 127.3, 127.5, 129.1, 129.3, 129.6, 133.9, 135.0, 135.2, 135.4, 146.4, 146.8, 156.2. FT-IR (film, cm-1) \\ 2974, 1690, 1391, 1158, 1111, 790, 737, 699. HRMS (ESI-TOF) m/z [M+Na]+ calcd for C27H31NO2SiNa 452.2016; found 452.1995.
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HC H
B H
A H
G H
L H
M H
H H
I
MeA Me
B
HF
H
E H
F
NMeA
HM
HH
HG
HI
HL
HD
HEHF HB
HA
MeB
HC
HC
HB
HA
HG
HL H
M H
H H
I
MeB Me
A
HG
- MeA
HG
- HM
H
G - H
H
HG
- HC
MeB-H
A
HC- H
H
HCHD
HEHF HB
HA
MeB
NHI
HH
MeA
HM
HL
HG
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HC
HB
HA
HD
HE
Me
MeA
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GC analysis of racemic and enantioenriched 3a.
NMe
Cycloβdex, iso 90°C, length 30mt, i.d. 0.25
min16 18 20 22 24 26 28 30 32 34
pA
4
6
8
10
12
FID1 A, (RENDINO\AZETID_PH000021.D)
27.81
3 28
.479
min14 16 18 20 22 24 26 28 30
pA
10
20
30
40
FID1 A, (RENDINO\AZET-NMETCHIR29.D)
Area: 659.
098 23.47
9
Area: 70.2
7
24.12
0
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HPLC analysis of racemic and enantioenriched 4h.
Cellulose – Lux1, Hexane – iPrOH 99:1, 0.5% Et2NH, 0.5 mL/min, 254 nm
N
HO
PhPh
min15 15.25 15.5 15.75 16 16.25 16.5 16.75
mAU
0
20
40
60
80
100
120
MWD1 B, Sig=254,4 Ref=360,100 (LUISI\ZE36Z3.D)
Area
: 321
6.66
15.
537
Area
: 319
2.72
16.
314
min15 15.5 16 16.5 17
mAU
0
20
40
60
80
100
120
MWD1 B, Sig=254,4 Ref=360,100 (LUISI\ZE43B.D)
Area
: 442
7.99
15.
440
Area
: 211
.648
16.
096
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HPLC analysis of racemic and enantioenriched 8.
Cellulose – Lux1, Hexane – iPrOH 90:10, 0.3% Et2NH, 1.0 mL/min, 254 nm
OPh Ph
HN
min6.5 6.75 7 7.25 7.5 7.75 8 8.25 8.5
mAU
0
50
100
150
200
250
300
MWD1 B, Sig=254,4 Ref=360,100 (LUISI\ZE44D.D)
Area
: 432
5.56
6.7
64
Area
: 453
4.51
7.9
07
min6.6 6.8 7 7.2 7.4 7.6 7.8
mAU
0
50
100
150
200
MWD1 B, Sig=254,4 Ref=360,100 (LUISI\ZE59C.D)
Area
: 324
2.56
6.7
90
Area
: 87.2
359
7.7
06
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X-Ray Analysis of N-Methylazetidine 4h and N-Bocazetidine 10a.
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