Highly Efficient One-Pot Synthesis of Hetero-Sequenced ... · S1# # Highly Efficient One-Pot Synthesis of Hetero-Sequenced Shape-Persistent Macrocycles through Orthogonal Dynamic

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Highly Efficient One-Pot Synthesis of Hetero-Sequenced Shape-Persistent Macrocycles through Orthogonal Dynamic Covalent Chemistry (ODCC) Kenji Okochi‡, Yinghua Jin‡, and Wei Zhang*

Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309.

Supporting Information

List of Contents

1. Materials and Synthetic Methods S2 2. Experimental Procedures S2-S6 3. Reaction progress of trial 1 and trial 3 as monitored by 1H NMR S7 4. NMR spectra of selected compounds S8-S15

Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2012

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1. Materials and Synthetic Methods

Reagents and solvents were purchased from commercial suppliers and used without further purification, unless otherwise indicated. Ether, tetrahydrofuran, toluene, CH2Cl2 and DMF are purified by MBRAUN solvent purification systems. 1-bromo-3,5-dinitrobenzene1 was prepared as previously described in the literature. All reactions were conducted in oven dried glassware. Unless otherwise specified, solvents were evaporated using a rotary evaporator after workup. Unless otherwise specified, the purity of the compounds was ≥ 95 % based on 1H NMR spectral integration. Flash column chromatography was performed by using a 100-150 times weight excess of flash silica gel 32-63 µm from Dynamic Absorbants Inc. Fractions were analyzed by TLC using TLC silica gel F254 250 µm precoated-plates from Dynamic Absorbants Inc. Analytical gel permeation chromatography (GPC) was performed using a Viscotek GPCmaxTM, a Viscotek Model 3580 Differential Refractive Index (RI) Detector, a Viscotek Model 3210 UV/VIS Detector and a set of two Viscotek Viscogel columns (7.8 × 30 cm, l- MBLMW-3078, and l-MBMMW-3078 columns) with THF as the eluent at 30 °C. The analytical GPC was calibrated using monodisperse polystyrene standards. MALDI Mass spectra were obtained on the Voyager-DE™ STR Biospectrometry Workstation using sinapic acid as the matrix. 1H NMR spectra were taken on Inova 400 and Inova 500 spectrometers. 13C NMR spectra were taken on Inova 400 and Bruker 300 spectrometers. CHCl3 was the solvent in all cases and 7.26 ppm was used as internal references for 1H NMR and 77.23 ppm for 13C NMR. 1H NMR data were reported in order: chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), number of protons, coupling constants (J, Hz). 2. Experimental Procedures

3-Bromo-5-hexadecylbenzaldehyde: To a Schlenk tube were added 1-tetradecene (0.48 mL, 1.51 mmol) and THF (3 mL) under nitrogen atmosphere and the solution was cooled to 0 °C using an ice bath. A solution of 9-BBN (1.0 M in THF, 3.02 mL, 1.51 mmol) was added drop-wise at 0 °C. The colorless solution was stirred for 1 hours at 0 oC and at rt for 6 h. The Schlenk tube was transferred to the glove box, and 3-bromo-5-iodobenzaldehyde (392 mg, 1.26 mmol), K2CO3 (348 mg, 2.52 mmol), Pd(PPh3)4 (44 mg, 0.038 mmol), and DMF (6 mL) were added. The mixture was heated at 80 °C for 24 hours. The reaction was cooled to r.t. and the volatiles were removed by rotary evaporation. The remaining solution was diluted with ethyl acetate (50 mL), and washed with water (5 x 50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude product was purified by flash column chromatography using 2 % EtOAc/hexane to yield the product as a soft white solid (277 mg, 57 %): 1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 7.82 (t, J = 1.7 Hz, 1H), 7.61 (t, J = 1.5 Hz, 1H), 7.58 (t, J = 1.8 Hz, 1H), 2.72 – 2.54 (m, 2H), 1.62 (m, 2H), 1.38 – 1.20 (m, 22H), 0.91 – 0.83 (m, 3H); 13C NMR (75

1 H. Jian, J. Tour, J. Org. Chem. 2005, 70, 3396-‐3424.


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MHz, CDCl3) δ 191.01, 146.23, 137.94, 137.31, 129.96, 128.24, 123.10, 35.38, 31.92, 31.06, 29.69, 29.67, 29.65, 29.62, 29.51, 29.39, 29.36, 29.14, 22.69, 14.12; HR-MS (ESI): Calc’d for C21H33BrO [M+] 381.1782; Found 381.1787.

3-Tetradecyl-5-vinylbenzaldehyde: A Schlenk tube was charged with 3-bromo-5-hexadecylbenzaldehyde (346 mg, 0.91 mmol), LiCl (15 mg, 0.36 mmol), and tributylvinylstannane (293 µL, 1.00 mmol) and transferred to the glove box where Pd(PPh3)4 (42 mg, 0.036 mmol) were added. The solids were dissolved in THF (5 mL), and the reaction was heated at 100 °C for 8 hours. It was then cooled to rt, and the volatiles were removed. The solids were dissolved in ethyl acetate (50 mL) and washed with a KF solution (1.0 M, 50 mL), and the KF solution was filtered to remove the stannane by-product. The filtrate was extracted with ethyl acetate (3 x 30 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated. The crude product was purified by flash column chromatography using 30 % dichloromethane/hexane as the eluent to yield the product as a white solid (199 mg, 67 %): 1H NMR (500 MHz, CDCl3) δ 10.01 (s, 1H), 7.74 (t, J = 1.7 Hz, 1H), 7.60 (t, J = 1.7 Hz, 1H), 7.52 – 7.40 (m, 1H), 6.76 (dd, J = 17.6, 10.9 Hz, 1H), 5.85 (d, J = 17.6 Hz, 1H), 5.36 (d, J = 10.9 Hz, 1H), 2.86 – 2.57 (m, 2H), 1.77 – 1.58 (m, 2H), 1.46 – 1.21 (m, 22H), 0.89 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 192.57, 144.25, 138.40, 136.80, 135.78, 132.36, 128.83, 125.03, 115.40, 35.63, 31.92, 31.28, 29.69, 29.68, 29.65, 29.55, 29.46, 29.36, 29.24, 22.69, 14.12; HR-MS (ESI): Calc’d for C23H36O [M+] 329.2848; Found 329.2843.

1-Bromo-3-(dodecyloxy)-5-nitrobenzene: This procedure reported by Moore et al was followed.2 A Schlenk tube was charged with 1-bromo-3,5-dinitrobenzene (977 mg, 3.96 mmol), dodecyl alcohol (1.50 g, 8.03 mmol), KOH (453 mg, 8.08 mmol), and DMF (3.7 mL). The mixture was heated at 90 °C for 20 hours. The resulting dark brown solution was cooled to r.t. and diluted with diethyl ether (100 mL). The ethereal solution was washed with water (4 x 50 mL), dried over anhydrous Na2SO4, and concentrated. The product was purified by flash column chromatography using 4 % EtOAC/hexane as the eluent to yield a light brown solid (955 mg, 62 %): 1H NMR (500 MHz, CDCl3) δ 7.95 (t, J = 1.8 Hz, 1H), 7.67 (t, J = 2.2 Hz, 1H), 7.36 (t, J = 2.0 Hz, 1H), 4.02 (t, J = 6.5 Hz, 2H), 1.95 – 1.73 (m, 2H), 1.57 – 1.41 (m, 2H), 1.42 – 1.16 (m, 16H), 0.89 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 160.18, 149.47, 124.30, 122.91, 118.68, 108.22, 69.21, 31.92, 29.65, 29.63, 29.56, 29.52, 29.35, 29.27, 28.87, 25.87, 22.69, 14.12; HR MS (ESI): Calc’d for C18H28BrNO3 [M+Na+] 408.1150; Found 408.1144.

2 C.S. Hartley, J. Moore, J. Am. Chem. Soc. 2007, 38, 11682-‐11683.


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1-(Dodecyloxy)-3-nitro-5-vinylbenzene: A Schlenk tube was charged with 1-bromo-3-(dodecyloxy)-5-nitrobenzene (613 mg, 1.59 mmol), LiCl (27 mg, 0.64 mmol), and tributylvinylstannane (513 µL, 1.75 mmol) and transferred to the glove box where Pd(PPh3)4 (73 mg, 0.064 mmol) were added. The solids were dissolved in THF (3 mL) and the reaction was heated at 100 °C for 6 hours. The reaction was cooled to r.t. and the all the volatiles were removed by rotary evaporation. The solids were redissolved in ethyl acetate (50 mL) and washed with a KF solution (1.0 M, 50 mL) and the KF solution was filtered to remove the stannane by-product. The filtrate was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over anhydrous Na2SO4, and concentrated. The crude product was purified by flash column chromatography using 4% EtOAc/hexanes at the eluent to yield a light brown solid (478 mg, 90 %): 1H NMR (500 MHz, CDCl3) δ 7.87 (t, J = 1.7 Hz, 1H), 7.61 (t, J = 2.2 Hz, 1H), 7.25 – 7.21 (m, 1H), 6.71 (dd, J = 17.5, 10.8 Hz, 1H), 5.87 (d, J = 17.5 Hz, 1H), 5.43 (d, J = 10.9 Hz, 1H), 4.04 (t, J = 6.5 Hz, 2H), 1.87 – 1.75 (m, 2H), 1.51 – 1.43 (m, 2H), 1.39 – 1.21 (m, 16H), 0.89 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 159.78, 149.43, 139.88, 134.89, 119.06, 116.94, 113.25, 107.61, 68.79, 31.93, 29.67, 29.65, 29.60, 29.56, 29.36, 29.34, 29.03, 25.96, 22.70, 14.11; HR MS (ESI): Calc’d for C20H21NO3 [M+] 334.2382; Found 334.2375.

3-(Dodecyloxy)-5-vinylaniline: A Schlenk tube was charged with 1-(dodecyloxy)-3-nitro-5-vinylbenzene (250 mg, 0.75 mmol), SnCl2 (726 mg, 3.75 mmol), and ethanol (7.5 mL). The reaction flask was heated at 95 °C for 75 minutes and then cooled to r.t.. The volatiles were removed by rotary evaporation and the solids were redissolved in ethyl acetate (50 mL). Aqueous NaOH (5.0 M, 50 mL) was added and the mixture was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash column chromatography using 20 % EtOAc/hexanes as the eluent to yield a light brown solid (193 mg, 85 %): 1H NMR (500 MHz, CDCl3) δ 6.59 (dd, J = 17.5, 10.8 Hz, 1H), 6.40 (t, J = 1.7 Hz, 1H), 6.36 (d, J = 1.8 Hz, 1H), 6.18 (t, J = 2.2 Hz, 1H), 5.69 (d, J = 17.5 Hz, 1H), 5.20 (d, J = 10.8 Hz, 1H), 3.93 (t, J = 6.6 Hz, 2H), 3.67 (s, 2H), 1.76 (p, J = 6.7 Hz, 2H), 1.50 – 1.40 (m, 2H), 1.39 – 1.19 (m, 16H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 160.66, 147.83, 139.83, 137.23, 114.01, 106.06, 103.14, 101.51, 68.09, 32.16, 29.91, 29.88, 29.85, 29.83, 29.64, 29.60, 29.54, 26.30, 22.94, 14.38. HR MS (ESI): Calc’d for C20H33NO [M+] 304.2640; Found 304.2633.


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Macrocycle 14: To a schlenk tube was added the a solution of 3-(dodecyloxy)-5-vinylaniline (50 mg, 0.16 mmol) and isophthalaldehyde (11 mg, 0.08 mmol) in 1,2,4-trichlorobenzene (3.5 mL). A solution of trifluoroacedic acid (0.75 mg, 0.007 mmol) in CH2Cl2 (10 µL) was added dropwise, and the yellowish solution was stirred at rt for 30 min. The reaction mixture was then stirred at ~0.2 mmHg for 30 min at rt. A solution of Grubbs-Hoveyda 2nd generation catalyst (10 mg, 0.016 mmol) in 1,2,4-TCB (0.5 mL) was added, and the greenish solution was heated at 50 oC for 16 h in the open argon atmosphere. The reaction was then cooled to rt and DIBAL-H (330 µL, 0.33 mmol, 1.0 M in CH2Cl2) was added. After stirring for 20 min at rt, the reaction was quenched with MeOH (a few drops), and satd. NaHCO3 (15 mL) was added. The mixture was stirred for 30 min and extracted with CH2Cl2 (3 x 50 mL). The combined organic extracts were dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash column chromatography (gradient elution, 20 % EtOAc/hexane → 30 % EtOAc/hexane) to provide cyclic hexamer 14 (46 mg, 85 %): 1H NMR (400 MHz, CDCl3) δ 7.43 – 7.21 (m, 10H), 6.87 (s, 4H), 6.44 (s, 4H), 6.33 (s, 4H), 6.13 (br s, J = 14.2 Hz, 4H), 4.33 (s, 8H), 4.05 (s, 4H), 3.95 (t, J = 6.5 Hz, 8H), 1.81 – 1.73 (m, 8H), 1.49 – 1.41 (m, 8H), 1.37 – 1.26 (m, 64H), 0.90 (t, J = 6.7 Hz, 12H); 13C NMR (101 MHz, CDCl3) δ 160.70, 149.56, 140.14, 139.41, 129.24, 129.07, 126.42, 126.32, 104.23, 102.13, 99.39, 68.06, 48.27, 32.14, 29.91, 29.87, 29.85, 29.67, 29.59, 26.32, 22.92, 14.36; MS (MALDI) calc’d for C92H136N4O4 ([M]+) 1362.06, found 1362.56.

Macrocycle 15: The procedure for the synthesis of macrocycle 14 was followed. 3-(Dodecyloxy)-5-vinylaniline (50 mg, 0.16 mmol) and 1,4-phthalaldehyde (11 mg, 0.08 mmol)


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were converted to compound 15 (38 mg, 68 %) using 1,2,4-trichlorobenzene (4.0 mL), trifluoroacedic acid (0.75 mg, 0.007 mmol), Grubbs-Hoveyda 2nd generation catalyst (10 mg, 0.016 mmol), and DIBAL-H (330 µL, 0.33 mmol, 1.0 M in CH2Cl2). Physical data for 15: 1H NMR (500 MHz, CDCl3) δ 7.36 (s, 12H), 6.87 (s, 6H), 6.44 (s, 6H), 6.35 (s, 6H), 6.14 (br s, 6H), 4.33 (s, 12H), 4.03 (s, 6H), 3.94 (t, J = 6.6 Hz, 12H), 1.80 – 1.75 (m, 12H), 1.48 – 1.43 (m, 12H), 1.37 – 1.24 (m, 96H), 0.90 (t, J = 6.9 Hz, 18H); 13C NMR (101 MHz, CDCl3) δ 160.73, 149.67, 149.60, 139.39, 138.60, 129.24, 128.10, 104.42, 102.10, 99.23, 68.06, 48.24, 32.14, 29.90, 29.87, 29.85, 29.83, 29.66, 29.58, 26.31, 22.92, 14.36; MS (MALDI) calc’d for C138H204N6O6 ([M+H]+) 2042.59, found 2043.66.

Macrocycle 16: The procedure for the synthesis of macrocycle 14 was followed. 3-(Dodecyloxy)-5-vinylaniline (42 mg, 0.14 mmol) and aldehyde 7 (29 mg, 0.14 mmol) were converted to compound 16 (42 mg, 64 %) using 1,2,4-trichlorobenzene (3.0 mL), trifluoroacedic acid (0.64 mg, 0.006 mmol), Grubbs-Hoveyda 2nd generation catalyst (8.7 mg, 0.014 mmol), and DIBAL-H (420 µL, 0.42 mmol). Physical data for 16: 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 8.1 Hz, 4H), 7.46 (d, J = 7.0 Hz, 2H), 7.42 – 7.32 (m, 6H), 7.30 (d, J = 8.0 Hz, 4H), 6.93 – 6.78 (m, 4H), 6.39 (s, 2H), 6.01 (t, J = 2.0 Hz, 2H), 5.76 (s, 2H), 4.38 (s, 4H), 3.91 (t, J = 6.6 Hz, 4H), 3.70 (s, 2H), 1.78 – 1.73 (m, 4H), 1.47 – 1.41 (m, 4H), 1.34 – 1.25 (m, 32H), 0.89 (t, J = 7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 160.32, 149.14, 141.78, 140.31, 138.90, 137.62, 136.85, 130.40, 129.77, 129.74, 129.60, 128.01, 127.84, 127.73, 126.52, 104.81, 102.79, 100.92, 68.08, 47.44, 32.15, 29.91, 29.87, 29.85, 29.83, 29.66, 29.58, 26.31, 22.92, 14.35; MS (MALDI) calc’d for C66H82N2O2 ([M]+) 935.37, found 935.56.


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3. Reaction progress of trial 1 and trial 3 as monitored by 1H NMR

Fig. S1 Reaction progress of trial 1: (a) addition of TFA, followed by HG2, after 18 h, rt; (b) after DIBAL-H reduction; (e) after purification. Only very weak signals of terminal vinyl groups were observed in the 1H NMR spectrum after 18 h at rt, indicating the simultaneous proceedings of imine metathesis and olefin metathesis in one pot.

Fig. S2 Reaction progress of trial 3: (a) addition of TFA, 30 min, rt; (b) addition of HG2, after 18 h, rt; (c) after 3 d; (d) after DIBAL-H reduction; (e) after purification. Without applying vacuum, after stirring 18 h at rt in the presence of HG2, there was no terminal vinyl group observed on 1H NMR spectrum.

b

c

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4. NMR spectra of selected compounds


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Highly Efficient One-Pot Synthesis of Hetero-Sequenced ... · S1# # Highly Efficient One-Pot Synthesis of Hetero-Sequenced Shape-Persistent Macrocycles through Orthogonal Dynamic