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Mn(III)-Mediated Phosphonation-Azidation of Alkenes: A Facile Synthesis of β-Azidophosphonates
Jian Xu,a Xueqin Li,a Yuzhen Gao,a Liangliang Zhang,a Weizhu Chen,ab Hua Fang,b Guo Tang,*a and Yufen Zhaoa
Table of Contents 1. General and typical procedures for the synthesis of β-azidophosphonates and
5a-5d............................................................................................................................... S2 2. Control experiments for the possible reaction pathways.......................................... S4 3. Compounds list...............................................................................................................S5 4. Spectral data...................................................................................................................S6 5. 1H and 13C NMR spectra........................................................................................... ...S15
Electronic Supplementary Material (ESI) for ChemComm.This journal is © The Royal Society of Chemistry 2015
2
General and Experimental Section General All reactions were carried out under nitrogen. Unless otherwise noted, materials were obtained from commercial suppliers and used without further purification. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were measured on Bruker AVⅢ 400M spectrometers with CDCl3 as solvent and tetramethylsilane (TMS) as internal standard or 85% H3PO4 as external standard for 31P NMR (162 MHz). Chemical shifts were reported in units (ppm) by assigning TMS resonance in the 1H spectrum as 0.00 ppm and CDCl3 resonance in the 13C spectrum as 77.23 ppm. All coupling constants (J values) were reported in Hertz (Hz). Column chromatography was performed on silica gel 300-400 mesh. The CAS number of the known compound was listed. The unknown products were further characterized by HRMS(FT-ICR-MS). Typical procedure for the synthesis of β-azidophosphonates: An oven-dried Schlenk tube containing Mn(OAc)3·2H2O (1.0 mmol) were evacuated and purged with nitrogen three times. Alkene (0.40 mmol), P(O)H (0.6 mmol), and TMSN3 (0.8 mmol) all were dissolved in NMP (3.0 mL) and added to the system at room temperature. The reaction mixture was heated with stirring at 55 oC for 12 hours. The reaction solution was concentrated in vacuo and then added 10 mL of saturated sodium bicarbonate solution and extracted with EtOAc (3×10 mL). The combined organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using petroleum ether–AcOEt (15:1-5:1, v/v) as the eluent to give the corresponding products. Synthesis of diethyl 2-(4-tert-butylbenzylamino)-2-phenylethylphosphonate (5b)
PPh3 (58 mg, 0.22 mmol) and 4a (56.6 mg, 0.2 mmol in THF:H2O (3:1, 1 mL) was stirred for 12 h at room temperature. The mixture was extracted with ethyl acetate (3×5 mL), and the combined organic layers were washed with brine, dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (5:1, v/v) as the eluent to give the corresponding product 5a(44 mg, 85%). Synthesis of diethyl 2-(4-tert-butylbenzylamino)-2-phenylethylphosphonate (5b)
PPh3 (58 mg, 0.22 mmol) and 4a (56.6 mg, 0.2 mmol in THF (1 mL) was stirred for 2 h at room
3
temperature. 4-(tert-butyl)benzaldehyde (0.26 mmol) was added and the mixture was heated at 60 °C for 10 h. The mixture was cooled to room temperature and MeOH (0.5 mL) was added followed by NaBH4 (15 mg, 0.4 mmol). After stirring for 1 h at room temperature, water (1 mL, mixed with 100 mL of AcOH) was added and stirred for 15 min. The mixture was extracted with ethyl acetate (3×5 mL), and the combined organic layers were washed with brine, dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether–AcOEt (5:1, v/v) as the eluent to give the corresponding product 5b (57 mg, 70%). Synthesis of dimethyl 2-(diethoxyphosphoryl)-1-phenylethyl(methyl)phosphoramidate(5c)
In an oven-dried, two-necked round bottom flask, 4a was dissolved in dry benzene (0.6 mmol/mL) and 1.0 equivalents of trimethyl phosphite was added. The reaction mixture was refluxed for 2 h at 80 °C. After cooling to room temperature, 1 mol% of BF3•EtO2 dissolved in 1 mL of dry benzene, was added to the reaction mixture and the rearrangement was allowed to proceed for 2 h at 80 °C. The solvent was removed under reduced pressure to give the crude product. The residue was purified by silica gel column chromatography using petroleum ether–AcOEt (5:1, v/v) as the eluent to give the corresponding product 5c (52%). Synthesis of diethyl 2-phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethylphosphonate (5d)
To a solution of azide 4a (56.6 mg, 0.2 mmol) in t-BuOH:H2O (1:1, 1 mL) at room temperature was added CuSO4﹒5H2O (1.5 mg, 0.01 mmol) and sodium carbonate (4 mg, 0.02 mmol) and ethynylbenzene (24.5 mg, 0.24 mmol). The reaction mixture was stirred for 12 h at room temperature and the solvents were removed under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether–AcOEt (5:1, v/v) as the eluent to give the corresponding product 5c (65 mg, 84%).
4
Control experiments for the possible reaction pathways
PR2
R1O
H
A
PR2
R1O
R
BR
PO R1
R2
CR
PO R1
R2
R
TMSN3
RPO
R1
R2
N3++ TMSN3
oxidation
oxidation
N3path a
path b
1) No desired product 4a was obtained when 2.0 equiv of TEMPO was added in the reaction under the optimal conditions. This result suggests that the radical was intercepted by TEMPO. However, no TEMPO-N3 was separated.
2) When N,N-diallyl-4-methylbenzenesulfonamide reacted with TMSN3 under the optimal
conditions, no substituted pyrrolidine was obtained, and N,N-diallyl-4-methylbenzenesulfonamide was recovered quantitatively.
NTs N
Ts
N3
+ TMSN3
not detected
0.2 mmol 0.4 mmolNMP(3 mL),55 oC, 12 h
Mn(OAc)3 2H2O(0.5 mmol )
3) TMSCN and TMCN easily produced anions of SCN and CN. When TMSN3 was replaced
with TMSCN or TMCN, no 6a or 8a was obtained under our condition.
0.6 mmol 0.8 mmol0.4 mmol
Ph TMSSCNH PO OEt
OEt PhPO OEt
OEt
SCN++
1a 2a 5a 6anot detected
NMP(3 mL),55 oC, 12 h
Mn(OAc)3 2H2O(1.0 mmol )
According to the above four control experiments, trapping the N3 radical was failed. However, we couldn’t exclude that N3 radical finishes the reaction. So we proposed two pathways (path a and path b) for this reaction. Path a was reported in many literatures (RSC Adv. 2014, 4, 51776–51779; Chem. Commun. 2015, 51, 1605–1607).
5
Compounds list No. compound page No. compound page 4a
S14 4p
329
4b
S15 4q
S30
4c
S16 4r
S31
4d
S17 4s
S32
4e
S18 4t
S33
4f
S19 4u
S34
4g
S20 4v
S35
4h
S21 4w
S36
4i
S22 4x
S37
4j P
N3 OOEt
OEtBr
S23 4y P
N3 OPh
OEt
S38
4k
S24 4z P
N3 OPh
Ph
S39
4l
S25 5a
S40
4m
S26 5b
S41
4n
S27 5c
S42
4o
S28 5d
S43
6
Spectral data Diethyl (2-azido-2-phenylethyl)phosphonate (4a)
1H NMR (400 MHz, CDCl3, ppm) δ 7.41 – 7.34 (m, 5 H), 4.90 – 4.84 (m, 1 H), 4.15 – 3.90 (m, 4 H), 2.41 – 2.30 (m, 1 H), 2.27 – 2.17 (m, 1 H), 1.31 – 1.21 (m, 6 H); 13C NMR (100 MHz, CDCl3, ppm) δ 139.1 (d, J = 10.9 Hz), 129.0, 128.8, 126.9, 62.1 (d, J = 6.4 Hz), 61.9 (d, J = 6.5 Hz), 61.0 (d, J = 1.7 Hz), 33.3 (d, J = 141.6 Hz), 16.3 (m); 31P NMR (162 MHz, CDCl3, ppm) δ 26.08; HRMS-ESI: m/z 306.0982 ([M+Na]+, C12H18N3NaO3P +
calcd. 306.0983). Diethyl (2-azido-2-o-tolyl)ethyl)phosphonate (4b)
1H NMR (400 MHz, CDCl3, ppm) δ 7.27 (t, J = 6.9 Hz, 1 H), 7.15 (s, 3 H), 4.82 (d, J = 7.5 Hz, 1 H), 4.11 – 3.95 (m, 4 H), 2.36 – 2.15 (m, 5 H), 1.31 – 1.21 (m, 6 H); 13C NMR (100 MHz, CDCl3, ppm) δ 139.0 (d, J = 11.1 Hz), 138.6 , 129.4 , 128.8 , 127.4 , 123.8 , 61.9 (d, J = 6.4 Hz), 61.7 (d, J = 6.5 Hz), 60.9 , 33.2 (d, J = 141.6 Hz), 21.3 , 16.2 (m); 31P NMR (162 MHz, CDCl3, ppm) δ 26.07; HRMS-ESI: m/z 320.1143 ([M+Na]+, C13H20N3NaO3P +
calcd. 320.1140). Diethyl (2-azido-2-(m-tolyl)ethyl)phosphonate (4c)
1H NMR (400 MHz, CDCl3, ppm) δ 7.27 (t, J = 7.9 Hz, 1 H), 7.15 (t, J = 7.5 Hz, 3 H), 4.86 – 4.80 (m, 1 H), 4.13 – 3.93 (m, 4 H), 2.37 – 2.19 (m, 5 H), 1.31 – 1.21 (m, 6 H); 13C NMR (100 MHz, CDCl3, ppm) δ 139.0 (d, J = 11.1 Hz), 138.8 , 129.5 , 128.9 , 127.5 , 123.9 , 62.0 (d, J = 6.4 Hz), 61.8 (d, J = 6.5 Hz), 61.0 (d, J = 1.8 Hz), 33.3 (d, J = 140.3 Hz), 21.4 , 16.3 (m); 31P NMR (162 MHz, CDCl3, ppm) δ 26.14; HRMS-ESI: m/z 320.1141 ([M+Na]+, C13H20N3NaO3P +
calcd. 320.1140). Diethyl (2-azido-2-(p-tolyl)ethyl)phosphonate (4d)
1H NMR (400 MHz, CDCl3, ppm) δ 7.24 – 7.18 (m, 4 H), 4.86 – 4.80 (m, 1 H), 4.13 – 3.92 (m, 4 H), 2.37 – 2.29 (m, 4 H), 2.25 – 2.15 (m, 1 H), 1.31 – 1.22 (m, 6 H); 13C NMR (100 MHz, CDCl3,
7
ppm) δ 138.5, 135.9 (d, J = 11.3 Hz), 129.5, 126.7, 61.9 (d, J = 6.5 Hz), 61.7 (d, J = 6.5 Hz), 60.6 (d, J = 1.9 Hz), 33.1 (d, J = 141.1 Hz), 21.1, 16.2 (m); 31P NMR (162 MHz, CDCl3, ppm) δ 26.16; HRMS-ESI: m/z 320.1136 ([M+Na]+, C13H20N3NaO3P +
calcd. 320.1140). Diethyl (2-azido-2-(4-(tert-butyl)phenyl)ethyl)phosphonate (4e)
N3PO
OEt
OEt
1H NMR (400 MHz, CDCl3, ppm) δ 7.40 (d, J = 8.3 Hz, 2 H), 7.27 (d, J = 8.3 Hz, 2 H), 4.87 – 4.81 (m, 1 H), 4.13 – 4.05 (m, 2 H), 4.02 – 3.89 (m, 2 H), 2.40 – 2.30 (m, 1 H), 2.27 – 2.17 (m, 1H), 1.32 – 1.19 (m, 15 H); 13C NMR (100 MHz, CDCl3, ppm) δ 151.8, 136.1 (d, J = 10.9 Hz), 126.6, 125.8, 62.0 (d, J = 6.5 Hz), 61.8 (d, J = 6.6 Hz), 60.7, 34.7, 33.2 (d, J = 141.1 Hz), 31.3, 16.3 (m); 31P NMR (162 MHz, CDCl3, ppm) δ 26.17; HRMS-ESI: m/z 340.1787 ([M+H]+, C16H27N3O3P +
calcd. 340.1790). Diethyl (2-azido-2-(4-methoxyphenyl)ethyl)phosphonate (4f)
PN3 O
OEtOEt
MeO 1H NMR (400 MHz, CDCl3, ppm) δ 7.27 (d, J = 8.6 Hz, 2 H), 6.91 (d, J = 8.7 Hz, 2 H), 4.86 – 4.80 (m, 1 H), 4.15 – 3.88 (m, 4 H), 3.81 (s, 3 H), 2.39 – 2.29 (m, 1 H), 2.23 – 2.15 (m, 1 H), 1.31 – 1.22 (m, 6 H); 13C NMR (100 MHz, CDCl3, ppm) δ 159.9, 131.1 (d, J = 10.1 Hz), 128.2, 114.3, 62.1 (d, J = 6.5 Hz), 61.9 (d, J = 6.5 Hz), 60.6 , 55.4, 33.2 (d, J = 139.2 Hz), 16.4 (m); 31P NMR (162 MHz, CDCl3, ppm) δ 26.18; HRMS-ESI: m/z 336.1086 ([M+Na]+, C13H20N3NaO4P +
calcd. 336.1089). Diethyl (2-azido-2-(3-nitrophenyl)ethyl)phosphonate (4g)
1H NMR (400 MHz, CDCl3, ppm) δ 8.25 – 8.22 (m, 2 H), 7.72 (d, J = 7.8 Hz, 1 H), 7.61 (d, J = 7.8 Hz, 1 H), 5.04 – 4.99 (m, 1 H), 4.15 – 3.98 (m, 4 H), 2.41 – 2.33 (m, 1 H), 2.25 – 2.18 (m, 1 H), 1.32 – 1.23 (m, 6 H); 13C NMR (100 MHz, CDCl3, ppm) δ 148.6, 141.5 (d, J = 10.3 Hz), 133.1, 130.1, 123.7, 122.0, 62.4 (d, J = 6.3 Hz), 62.1 (d, J = 6.6 Hz), 60.4, 33.5 (d, J = 141.9 Hz), 16.4 (m); 31P NMR (162 MHz, CDCl3, ppm) δ 24.71; HRMS-ESI: m/z 351.0835 ([M+Na]+, C12H17N4NaO5P +
calcd. 351.0834). 4-(1-Azido-2-(diethoxyphosphoryl)ethyl)phenyl acetate (4h)
8
1H NMR (400 MHz, CDCl3, ppm) δ 7.36 (d, J = 8.5 Hz, 2 H), 7.12 (d, J = 8.5 Hz, 2 H), 4.91 – 4.85 (m, 1 H), 4.15 – 3.90 (m, 4 H), 2.38 – 2.28 (m, 4 H), 2.23 – 2.14 (m, 1 H), 1.31 – 1.22 (m, 6 H); 13C NMR (100 MHz, CDCl3, ppm) δ 169.2 , 150.8 , 136.7 (d, J = 10.7 Hz), 127.9, 122.1, 62.0 (d, J = 6.4 Hz), 61.9 (d, J = 6.5 Hz), 60.5, 33.4 (d, J = 142.6 Hz), 21.1, 16.3 (m); 31P NMR (162 MHz, CDCl3, ppm) δ 25.62 ; HRMS-ESI: m/z 342.1216 ([M+H]+, C14H21N3O5P +
calcd. 342.1219). Diethyl (2-azido-2-(4-chlorophenyl)ethyl)phosphonate (4i)
1H NMR (400 MHz, CDCl3, ppm) δ 7.29 (d, J = 8.5 Hz, 2 H), 7.22 (d, J = 8.5 Hz, 2 H), 4.81 – 4.75 (m, 1 H), 4.08 – 3.84 (m, 4 H), 2.29 – 2.23 (m, 1 H), 2.15 – 2.05 (m, 1 H), 1.24 – 1.14 (m, 6 H); 13C NMR (100 MHz, CDCl3, ppm) δ 137.6 (d, J = 10.6 Hz), 134.6, 129.1, 128.3, 62.1 (d, J = 6.3 Hz), 61.9 (d, J = 6.5 Hz), 60.3 (d, J = 1.4 Hz), 33.3 (d, J = 141.5 Hz), 16.3 (m); 31P NMR (162 MHz, CDCl3, ppm) δ 25.48; HRMS-ESI: m/z 318.0779 ([M+H]+, C12H18ClN3O3P+
calcd. 318.0774). Diethyl (2-azido-2-(4-bromophenyl)ethyl)phosphonate (4j)
1H NMR (400 MHz, CDCl3, ppm) δ 7.53 (d, J = 8.4 Hz, 2 H), 7.23 (d, J = 8.4 Hz, 2 H), 4.87 – 4.81 (m, 1 H), 4.15 – 3.92 (m, 4 H), 2.36 – 2.26 (m, 1 H), 2.22 – 2.13 (m, 1 H), 1.31 – 1.22 (m, 6 H); 13C NMR (100 MHz, CDCl3, ppm) δ 138.2 (d, J = 10.6 Hz), 132.2, 128.6, 122.8, 62.2 (d, J = 6.5 Hz), 61.9 (d, J = 6.6 Hz), 60.5 (d, J = 1.3 Hz), 33.3 (d, J = 141.3Hz), 16.4 (m); 31P NMR (162 MHz, CDCl3, ppm) δ 25.45; HRMS-ESI: m/z 362.0270 ([M+H]+, C12H18BrN3O3P +
calcd. 362.0269). Diethyl (2-azido-2-(2-bromophenyl)ethyl)phosphonate (4k)
PN3 O
OEtOEt
Br 1H NMR (400 MHz, CDCl3, ppm) δ 7.60 – 7.58 (m, 1 H), 7.47 – 7.45 (m, 1 H), 7.37 (t, J = 7.8 Hz, 1 H), 7.21 – 7.17 (d, J = 7.7 Hz, 1 H), 5.40 – 5.34 (m, 1 H), 4.17 – 4.08 (m, 4 H), 2.34 – 2.27 (m, 1 H), 2.25 – 2.21 (m, 1 H), 1.34 – 1.30 (m, 6 H); 13C NMR (100 MHz, CDCl3, ppm) δ 138.7 (d, J = 13.1 Hz), 133.3, 129.9, 128.1, 127.9, 122.8, 62.1 (d, J = 6.4 Hz), 61.9 (d, J = 6.5 Hz), 59.8 (d, J = 3.2 Hz), 33.4 (d, J = 142.1 Hz), 16.4 (d, J = 6.2 Hz); 31P NMR (162 MHz, CDCl3, ppm) δ 25.35; HRMS-ESI: m/z 362.0270 ([M+H]+, C12H18BrN3O3P +
calcd. 362.0269).
9
Diethyl (2-azido-2-(4-fluorophenyl)ethyl)phosphonate (4l)
1H NMR (400 MHz, CDCl3, ppm) δ 7.28 – 7.25 (m, 2 H), 7.01 (t, J = 8.7 Hz, 2 H), 4.82 – 4.76 (m, 1 H), 4.07 – 3.83 (m, 4 H), 2.31 – 2.20 (m, 1 H), 2.16 – 2.06 (m, 1 H), 1.23 – 1.13 (m, 6 H); 13C NMR (100 MHz, CDCl3, ppm) δ 162.7 (d, J = 248.7 Hz), 134.9 (d, J = 3.1 Hz), 134.8 (d, J = 3.2 Hz), 128.7 (d, J = 8.3 Hz), 115.7 (d, J = 21.6 Hz), 62.0 (d, J = 6.5 Hz), 61.8 (d, J = 6.5 Hz), 60.2 , 33.2 (d, J = 141.3 Hz), 16.2 (m); 31P NMR (162 MHz, CDCl3, ppm) δ 25.6; HRMS-ESI: m/z 324.0886 ([M+Na]+, C12H17FN3NaO3P +
calcd. 324.0889). Diethyl (2-azido-2-(3-fluorophenyl)ethyl)phosphonate (4m)
1H NMR (400 MHz, CDCl3, ppm) δ 7.40 – 7.32 (m, 1 H), 7.14 (d, J = 7.7 Hz, 1 H), 7.09 – 7.03 (m, 2 H), 4.91 – 4.85 (m, 1 H), 4.14 – 3.94 (m, 4 H), 2.37 – 2.27 (m, 1 H), 2.24 – 2.14 (m, 1 H), 1.32 – 1.23 (m, 6 H); 13C NMR (100 MHz, CDCl3, ppm) δ 162.9 (d, J = 248.0 Hz), 141.7 (d, J = 6.7 Hz), 141.6 (d, J = 6.7 Hz), 130.6 (d, J = 8.3 Hz), 122.5 (d, J = 2.8 Hz), 115.6 (d, J = 21.0 Hz), 113.8 (d, J = 22.4 Hz), 62.1 (d, J = 6.5 Hz), 61.8 (d, J = 6.5 Hz), 60.4 , 33.3 (d, J = 140.4 Hz), 16.3 (m); 31P NMR (162 MHz, CDCl3, ppm) δ 25.47; HRMS-ESI: m/z 302.1069 ([M+H]+, C12H18FN3O3P+
calcd. 302.1070). Diethyl (2-azido-2-(naphthalene-2-yl)ethyl)phosphonate (4n)
1H NMR (400 MHz, CDCl3, ppm) δ 7.89 – 7.81 (m, 4 H), 7.53 – 7.44 (m, 3 H), 5.09 – 5.03 (m, 1 H), 4.14 – 3.89 (m, 4 H), 2.45 – 2.39 (m, 1 H), 2.35 – 2.25 (m, 1 H), 1.29 – 1.15 (m, 6 H); 13C NMR (100 MHz, CDCl3, ppm) δ 136.3 (d, J = 11.1 Hz), 133.3, 133.1, 129.1, 128.1, 127.7, 126.6, 126.6, 126.2, 124.0, 62.1 (d, J = 6.4 Hz), 61.8 (d, J = 6.4 Hz), 61.2 (d, J = 1.7 Hz), 33.2 (d, J = 141.2 Hz), 16.3 (d, J = 6.1 Hz), 16.2 (d, J = 6.2 Hz); 31P NMR (162 MHz, CDCl3, ppm) δ 25.86; HRMS-ESI: m/z 356.1142 ([M+Na]+, C16H20N3NaO3P +
calcd. 356.1140). Diethyl (2-azido-1,1-diphenylethyl)phosphonate (4o)
10
1H NMR (400 MHz, CDCl3, ppm) δ 7.29 – 7.23 (m, 8 H), 7.20 – 7.17 (m, 2 H), 3.89 – 3.77 (m, 2 H), 3.75 – 3.62 (m, 2 H), 2.99 (s, 1 H), 2.95 (s, 1 H), 1.08 – 1.05 (m, 6 H); 13C NMR (100 MHz, CDCl3, ppm) δ 142.8 (d, J = 8.8 Hz), 128.4, 127.8, 126.7, 69.0 (d, J = 4.6 Hz), 61.7 (d, J = 6.5 Hz), 36.6 (d, J = 145.6 Hz), 16.2 (d, J = 6.5 Hz); 31P NMR (162 MHz, CDCl3, ppm) δ 24.26; HRMS-ESI: m/z 382.1295 ([M+Na]+, C18H22N3NaO3P +
calcd. 382.1296). Diethyl (2-azido-2-phenylpropyl)phosphonate (4p)
1H NMR (400 MHz, CDCl3, ppm) δ 7.47 (d, J = 7.2 Hz, 2 H), 7.37 (t, J = 7.5 Hz, 2 H), 7.30 (d, J = 7.2 Hz, 1 H), 4.04 – 3.75 (m, 4 H), 2.41 (s, 1 H), 2.36 (s, 1 H), 1.94 (s, 3 H), 1.25 (t, J = 6.8 Hz, 3 H), 1.14 (t, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3, ppm) δ 143.1 (d, J = 7.9 Hz), 128.5, 127.8, 125.6, 63.8, 61.7 (d, J = 6.5 Hz), 61.4 (d, J = 6.5 Hz), 39.2 (d, J = 141.2 Hz), 25.4 (d, J = 3.8 Hz), 16.3 (d, J = 6.3 Hz), 16.1(d, J = 6.3 Hz);31P NMR (162 MHz, CDCl3, ppm) δ 24.52; HRMS-ESI: m/z 320.1139 ([M+Na]+, C13H20N3NaO3P +
calcd. 320.1140). Diethyl (2-azido-2-cyclopropyl-2-phenylethyl)phosphonate (4q)
N3
PO
EtOEtO
1H NMR (400 MHz, CDCl3, ppm) δ 7.52 (d, J = 7.7 Hz, 2 H), 7.38 (t, J = 7.9 Hz, 2 H), 7.30 (t, J = 7.5 Hz, 1 H), 4.05 – 3.83 (m, 3 H), 3.78 – 3.66 (m, 1 H), 2.70 – 2.61 (m, 1 H), 2.53 – 2.44 (m, 1 H), 1.86 – 1.79 (m, 1 H), 1.23 – 1.11 (m, 6 H), 0.67 – 0.57 (m, 2 H), 0.52 – 0.38 (m, 1 H); 13C NMR (100 MHz, CDCl3, ppm) δ 140.4 (d, J = 5.7 Hz), 128.3, 128.0, 126.9, 61.7 (d, J = 6.5 Hz), 61.6 (d, J = 6.6 Hz), 37.1 (d, J = 142.7 Hz), 20.3 (d, J = 6.9 Hz), 16.3 (m), 2.0 (d, J = 65.7 Hz); 31P NMR (162 MHz, CDCl3, ppm) δ 24.48; HRMS-ESI: m/z 346.1294 ([M+Na]+, C15H22N3NaO3P+
calcd. 346.1296). Diethyl (1-azido-2,3-dihydro-1H-inden-2-yl)phosphonate (4r)
1H NMR (400 MHz, CDCl3, ppm) δ 7.31 – 7.29 (m, 1 H), 7.22 – 7.15 (m, 3 H), 5.12 – 5.07 (m, 1 H), 4.12 – 4.04 (m, 4 H), 3.24 – 3.09 (m, 2 H), 2.67 – 2.61 (m, 1 H), 1.28 – 1.21 (m, 6 H); 13C
11
NMR (100 MHz, CDCl3, ppm) δ 140.8 (d, J = 10.4 Hz), 139.8 (d, J = 11.0 Hz), 129.1, 127.4, 124.8, 124.5, 66.8, 62.3 (m), 42.8 (d, J = 148.1 Hz), 32.0 , 16.5 (d, J = 3.4 Hz), 16.4 (d, J = 3.3 Hz); 31P NMR (162 MHz, CDCl3, ppm) δ 29.65; HRMS-ESI: m/z 318.0985 ([M+Na]+, C13H18N3NaO3P +
calcd. 318.0983). Diethyl (2-azido-2-(thiophen-2-yl)ethyl)phosphonate (4s)
1H NMR (400 MHz, CDCl3, ppm) δ 7.33 – 7.32 (m, 1 H), 7.08 (d, J = 2.9 Hz, 1 H), 7.01 – 6.99 (m, 1 H), 5.16 – 5.10 (m, 1 H), 4.15 – 4.3.97 (m, 4 H), 2.42 – 2.32 (m, 2 H), 1.33 – 1.25 (m, 6 H); 13C NMR (100 MHz, CDCl3, ppm) δ 142.0 (d, J = 13.3 Hz), 126.8, 126.0 (d, J = 3.5 Hz), 62.1 (d, J = 6.4 Hz), 61.9 (d, J = 6.4 Hz), 56.4, 33.8 (d, J = 142.0 Hz), 16.3(m); 31P NMR (162 MHz, CDCl3, ppm) δ 25.09; HRMS-ESI: m/z 312.0545 ([M+Na]+, C10H16N3NaO3PS +
calcd. 312.0548). Diethyl (2-azido-3-phenylpropyl)phosphonate (4t)
1H NMR (400 MHz, CDCl3, ppm) δ 7.33 (t, J = 7.5 Hz, 2 H), 7.28 – 7.26 (m, 1 H), 7.24 – 7.22 (m, 2 H), 4.17 – 4.07 (m, 4 H), 3.98 – 3.89 (m, 1 H), 3.00 – 2.95 (m, 1 H), 2.91 – 2.86 (m, 1 H), 2.02 – 2.00 (m, 1 H), 1.98 – 1.96 (m, 1 H), 1.35 – 1.31 (m, 6 H); 13C NMR (100 MHz, CDCl3, ppm) δ 136.8, 129.5, 128.8, 127.2, 62.1 (d, J = 6.6 Hz), 62.0 (d, J = 6.5 Hz), 59.0 (d, J = 3.3 Hz), 41.0 (d, J = 11.9 Hz), 30.9 (d, J = 141.9 Hz), 16.5 (d, J = 6.0 Hz); 31P NMR (162 MHz, CDCl3, ppm) δ 27.00; HRMS-ESI: m/z 320.1142 ([M+Na]+, C13H20N3NaO3P +
calcd. 320.1140). Diethyl (2-azidocyclohexyl)phosphonate (4u)
1H NMR (400 MHz, CDCl3, ppm) δ 4.20 – 4.10 (m, 4 H), 4.47 – 3.39 (m, 1 H), 2.16 – 1.75 (m, 7 H), 1.43 – 1.40 (m, 1 H), 1.37 – 1.33 (m, 6 H), 1.26 (s, 1 H); 13C NMR (100 MHz, CDCl3, ppm) δ 62.0 (d, J = 6.9 Hz), 60.0 (d, J = 5.9 Hz), 41.0 (d, J = 143.6 Hz), 32.1 (d, J = 12.5 Hz), 25.7 (d, J = 4.8 Hz), 24.8 (d, J = 14.1 Hz), 24.4, 16.6 (m); 31P NMR (162 MHz, CDCl3, ppm) δ 29.36; HRMS-ESI: m/z 284.1137 ([M+Na]+, C10H20N3NaO3P +
calcd. 284.1140). Diisopropyl (2-azido-2-phenylethyl)phosphonate (4v)
1H NMR (400 MHz, CDCl3, ppm) δ 7.36 – 7.34 (m, 5 H), 4.85 – 4.83 (m, 1 H), 4.71 – 4.61 (m, 2
12
H), 2.34 – 2.25 (m, 1 H), 2.23 – 2.13 (m, 1 H), 1.28 – 1.20 (m, 12 H); 13C NMR (100 MHz, CDCl3, ppm) δ 139.3 (d, J = 10.7 Hz), 128.9, 128.6, 126.9, 70.7 (d, J = 6.6 Hz), 70.5 (d, J = 6.7 Hz), 61.3, 34.5 (d, J = 142.0 Hz), 24.0 (m), 23.8 (m); 1P NMR (162 MHz, CDCl3, ppm) δ 23.77; HRMS-ESI: m/z 334.1296 ([M+Na]+, C14H22N3NaO3P +
calcd. 334.1296). Diisopropyl (2-azido-2-(4-fluorophenyl)ethyl)phosphonate (4w)
PN3 O
O
O
F 1H NMR (400 MHz, CDCl3, ppm) δ 7.27 – 7.24 (m, 2 H), 7.00 (t, J = 8.0 Hz, 2 H), 4.80 – 4.74 (m, 1 H), 4.68 – 4.48(m, 2 H), 2.26 – 2.18 (m, 1 H), 2.13 – 2.03 (m, 1 H), 1.23 – 1.19 (m, 9 H), 1.12 (d, J = 6.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3, ppm) δ 162.8 (d, J = 247.4 Hz), 135.2 (d, J = 9.9 Hz), 128.8 (d, J = 8.3 Hz), 115.8 (d, J = 21.7 Hz), 70.8 (d, J = 6.6 Hz), 70.6 (d, J = 6.7 Hz), 60.6, 34.7 (d, J = 124.5 Hz), 24.0 (m), 23.9 (m); 31P NMR (162 MHz, CDCl3, ppm) δ 23.45; HRMS-ESI: m/z 352.1201 ([M+Na]+, C14H21FN3NaO3P +
calcd. 352.1202). Dibenzyl (2-azido-2-phenylethyl)phosphonate (4x)
1H NMR (400 MHz, CDCl3, ppm) δ 7.37 – 7.24 (m, 15 H), 5.04 – 4.94 (m, 2 H), 4.90 – 4.79 (m, 3 H), 2.43 – 2.32 (m, 1 H), 2.29 – 2.19 (m, 1 H); 13C NMR (100 MHz, CDCl3, ppm) δ 138.7 (d, J = 11.1 Hz), 136.1 (d, J = 6.1 Hz), 136.0 (d, J = 6.1 Hz), 129.0, 128.8, 128.6 (d, J = 2.3 Hz), 128.5, 128.0 (d, J = 2.4 Hz), 126.8, 67.6 (d, J = 6.2 Hz), 67.4 (d, J = 6.3 Hz), 60.8 (d, J = 1.9 Hz), 33.6 (d, J = 141.6 Hz); 31P NMR (162 MHz, CDCl3, ppm) δ 27.17; HRMS-ESI: m/z 408.1476 ([M+H]+, C22H23N3O3P +
calcd. 408.1477). Ethyl (2-azido-2-phenylethyl)(phenyl)phosphinate (4y)
1H NMR (400 MHz, CDCl3, ppm) δ 7.82 – 7.77 (m, 1 H), 7.67 – 7.62 (m, 1 H), 7.56 – 7.46 (m, 2 H), 7.41 – 7.19 (m, 6 H), 4.97 – 4.86 (m, 1 H), 4.12 – 3.77 (m, 2 H), 2.63 – 2.48 (m, 1 H), 2.43 – 2.28 (m, 1 H), 1.31 – 1.18 (m, 3 H); 13C NMR (100 MHz, CDCl3, ppm) δ 139.2 (d, J = 10.5 Hz), 138.8 (d, J = 9.1 Hz), 132.4 (d, J = 2.5 Hz), 132.3 (d, J = 2.5 Hz), 131.6 (d, J = 10.1 Hz), 131.4 (d, J = 10.1 Hz), 130.1 (d, J = 34.6 Hz), 128.8 (d, J = 11.6 Hz), 128.7 (d, J = 12.2 Hz), 128.6 , 128.5 (d, J = 6.5 Hz), 126.7 (d, J = 3.6 Hz), 60.9 (d, J = 6.3 Hz), 60.7 (d, J = 6.1 Hz), 60.4 (d, J = 22.3 Hz), 37.5 (d, J = 22.8 Hz), 36.5 (d, J = 23.5 Hz), 16.4 (d, J = 6.5 Hz), 16.2 (d, J = 6.5 Hz); 31P NMR (162 MHz, CDCl3, ppm) δ 39.67 , 39.19; HRMS-ESI: m/z 316.1209 ([M+H]+, C16H19N3O2P +
calcd. 316.1215).
13
(2-Azido-2-phenylethyl)diphenylphosphine oxide (4z)
1H NMR (400 MHz, CDCl3, ppm) δ 7.84 – 7.79 (m, 2 H), 7.64 – 7.60 (m, 2 H), 7.55 – 7.42 (m, 4 H), 7.39 – 7.34 (m, 2 H), 7.29 – 7.24 (m, 5 H), 5.15 – 5.10 (m, 1 H), 2.94 – 2.84 (m, 1 H), 2.72 – 2.64 (m, 1 H); 13C NMR (100 MHz, CDCl3, ppm) δ 139.3 (d, J = 8.8 Hz), 133.3 (d, J = 16.3 Hz), 132.3 (d, J = 15.8 Hz), 131.9 (d, J = 2.7 Hz), 131.8 (d, J = 2.6 Hz), 130.8 (d, J = 9.5 Hz), 130.6 (d, J = 9.5 Hz), 128.9 , 128.7 (d, J = 6.4 Hz), 128.6 (d, J = 6.9 Hz), 126.8, 60.2 (d, J = 2.3 Hz), 37.4(d, J = 69.1 Hz); 31P NMR (162 MHz, CDCl3, ppm) δ 27.95; HRMS-ESI: m/z 348.1271 ([M+H]+, C20H19N3OP +
calcd. 348.1266). Diethyl (2-amino-2-phenylethyl)phosphonate (5a)
1H NMR (400 MHz, CDCl3, ppm) δ 7.38 (d, J = 7.4 Hz, 2 H), 7.33 (t, J = 7.7 Hz, 2 H), 7.25 (t, J = 7.1 Hz, 1 H), 4.44 – 4.38 (m, 1 H), 4.11 – 4.03 (m, 4 H), 2.21 (s, 2 H), 2.18 – 2.11 (m, 2 H), 1.30 (t, J = 7.0 Hz, 6 H); 13C NMR (100 MHz, CDCl3, ppm) δ 145.4 (d, J = 15.3 Hz), 128.7 , 127.5 , 126.2 , 61.7 (m), 51.2 (d, J = 3.7 Hz), 36.0 (d, J = 136.6 Hz), 16.5 (d, J = 2.3 Hz), 16.4 (d, J = 2.3 Hz); 31P NMR (162 MHz, CDCl3, ppm) δ 29.13; HRMS-ESI: m/z 280.1077 ([M+Na]+, C12H20NNaO3P +
calcd. 280.1078). Diethyl (2-((4-(tert-butyl)benzyl)amino)-2-phenylethyl)phosphonate (5b)
1H NMR (400 MHz, CDCl3, ppm) δ 7.42 (d, J = 7.4 Hz, 2 H), 7.39 – 7.34 (m, 4 H), 7.29 (t, J = 4.4 Hz, 1 H), 7.22 (d, J = 8.3 Hz, 2 H), 4.23 – 3.86 (m, 5 H), 3.63 (d, J = 13.4 Hz, 1 H), 3.50 (d, J = 13.0 Hz, 1 H), 2.29 – 2.19 (m, 1 H), 2.13 – 2.03 (m, 1 H), 1.33 (s, 9 H), 1.28 – 1.22 (m, 6 H); 13C NMR (100 MHz, CDCl3, ppm) δ 149.8 (s), 137.2 (s), 132.2 (d, J = 9.8 Hz), 128.7 (s), 128.0 (s), 127.6 (s), 127.2 (s), 125.3 (s), 61.8 (d, J = 6.7 Hz), 61.7 (d, J = 6.3 Hz), 57.0 (s), 51.0 (s), 35.7 (s), 34.5 (s), 31.5 (s), 16.5 (d, J = 4.0 Hz); 31P NMR (162 MHz, CDCl3, ppm) δ 28.83; HRMS-ESI: m/z 426.2171 ([M+Na]+, C23H34NNaO3P+
calcd. 426.2174). Dimethyl (2-(diethoxyphosphoryl)-1-phenylethyl)(methyl)phosphoramidate (5c)
14
1H NMR (400 MHz, CDCl3, ppm) δ 7.41 (d, J = 7.6 Hz, 2 H), 7.34 (t, J = 7.7 Hz, 2 H), 7.29 (d, J = 7.1 Hz, 1 H), 5.21 – 5.13 (m, 1 H), 4.06 – 3.95 (m, 4 H), 3.68 (d, J = 11.2 Hz, 3 H), 3.58 (d, J = 11.2 Hz, 3 H), 2.63 – 2.53 (m, 1 H), 2.46 (d, J = 9.6 Hz, 4 H), 1.27 – 1.19 (m, 6 H); 13C NMR (100 MHz, CDCl3, ppm) δ 139.1 (d, J = 8.0 Hz), 128.3, 128.1, 127.9, 61.9 (d, J = 6.6 Hz), 61.6 (d, J = 6.6 Hz), 55.0 (d, J = 5.7 Hz), 53.1 (d, J = 5.7 Hz), 52.9 (d, J = 5.8 Hz), 29.0 (d, J = 141.2 Hz), 28.0 (d, J = 3.6 Hz), 16.3 (m); 31P NMR (162 MHz, CDCl3, ppm) δ 27,33 , 11.63; HRMS-ESI: m/z 402.1209 ([M+Na]+, C15H27NNaO6P2
+ calcd. 402.1211).
Diethyl (2-phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethyl)phosphonate (5d)
1H NMR (400 MHz, CDCl3, ppm) δ 7.80 (d, J = 6.4 Hz, 3 H), 7.4 (d, J = 6.6 Hz, 2 H), 7.40 – 7.28 (m, 6 H), 6.02 – 6.00 (m, 1 H), 4.01 – 3.79 (m, 4 H), 3.34 – 3.24 (m, 1 H), 2.84 – 2.74 (m, 1 H), 1.19 – 1.11 (m, 6 H); 13C NMR (100 MHz, CDCl3, ppm) δ 147.7 (s), 138.6 (d, J = 9.6 Hz), 130.5 (s), 129.0 (d, J = 28.3 Hz), 128.5 (d, J = 81.3 Hz), 127.1 (s), 125.7 (s), 119.8 (s), 62.0 (d, J = 6.5 Hz), 60.6 (s), 33.1 (s), 31.7 (s), 16.2 (m); 31P NMR (162 MHz, CDCl3, ppm) δ 24.6; HRMS-ESI: m/z 408.1451 ([M+Na]+, C20H24N3NaO3P +
calcd. 408.1453).