K
E. Greve et al.
Paper
Synthesis
In a 50 mL oven-dried round-bottomed flask, a mixture of carbamate
4 (10.8 g, 35.8 mmol) and powdered KOH (3.01 g, 53.7 mmol) in an-
hyd DMSO (20 mL) was stirred at r.t. for 5 min. Then MeI (3.34 mL,
53.7 mmol) was slowly added and the reaction mixture was stirred at
r.t. for 48 h under N2. Aq NH4Cl (25%, 450 mL) was added and the
product was extracted with EtOAc (4 × 150 mL). The combined organ-
ic layers were washed with brine (100 mL), dried (Na2SO4), filtered,
and concentrated under vacuum to afford a yellow oil. The crude
material was purified by flash chromatography (340 g SiO2 column,
0–20% EtOAc/hexanes gradient) to yield carbamate 5 as a clear yellow
oil (9.8 g, 87%); Rf = 0.84 (50:50 EtOAc/hexanes).
1H NMR (300 MHz, CDCl3): δ = 7.30–7.25 (m, 1 H), 7.14–7.08 (m, 3 H),
3.84 (dd, J = 4.1, 2.6 Hz, 1 H), 3.42 (t, J =7.6 Hz, 2 H), 3.14 (dd, J =5.5,
4.1 Hz, 1 H), 2.83–2.78 (m, 6 H), 1.44–1.39 (m, 9 H).
13C NMR (75 MHz, CDCl3): δ = 155.7, 139.6, 137.8, 136.9, 128.7, 128.5,
126.9, 124.3, 113.9, 79.3, 50.9, 35.0, 34.6, 28.5.
HRMS (ESI+): m/z [M + Na]+ calcd for C16H23NO3Na: 300.1576; found:
300.1570.
tert-Butyl N-{2-[3-(1-Azido-2-hydroxyethyl)phenyl]ethyl}-
N-methylcarbamate (8)
NaN3 (504 mg, 7.75 mmol) was added to a stirred suspension of epox-
ide 7 (715 mg, 2.58 mmol) in H2O (12 mL) in a 25 mL round-bottomed
flask. The reaction mixture was heated at 60 °C in an oil bath for 32 h.
Then the flask was cooled to r.t., and H2O (10 mL) was added. The
aqueous phase was extracted with EtOAc (3 × 40 mL) and the com-
bined organic extracts were washed with brine (40 mL), dried (Na2SO4),
and concentrated under vacuum. The crude product was purified by
flash chromatography (100 g SiO2, 0–60% EtOAc/hexanes) to yield
azide 8 as a colorless oil (533 mg, 71%); Rf = 0.62 (50:50 EtOAc/hex-
anes).
IR (thin film): 2974, 2929, 1688, 1596, 1568, 1475, 1424, 1390, 1364,
1214, 1232, 772, 693, 664 cm–1. Note: some peaks are broad-
ened/doubled due to carbamate rotamers.
1H NMR (300 MHz, CDCl3): δ = 7.35–7.33 (m, 2 H), 7.18–7.09 (m, 2 H),
3.42 (t, J = 6.9 Hz, 2 H), 2.87–2.78 (m, 5 H), 1.44–1.38 (m, 9 H).
13C NMR (75 MHz, CDCl3): δ = 155.6, 141.7, 131.9, 130.1, 129.4, 127.7,
122.5, 79.5, 50.5, 34.3, 33.8, 28.4.
tert-Butyl N-[2-(3-Ethenylphenyl)ethyl]-N-methylcarbamate (6)
A solution of potassium vinyltrifluoroborate (2.10 g, 15.7 mmol),
PdCl2 (53.2 mg, 0.30 mmol), PPh3 (236 mg, 0.90 mmol), Cs2CO3 (14.7
g, 45.0 mmol), and aryl bromide 5 (4.71 g, 15.0 mmol) in THF/H2O
(9:1, 30 mL) was heated at 85 °C under an argon atmosphere in a 15
mL sealed pressure tube. The reaction mixture was stirred at 85 °C for
22 h, then cooled to r.t. and diluted with H2O (45 mL) followed by ex-
traction with CH2Cl2 (3 × 150 mL). The combined organic extracts
were washed with brine (50 mL), dried (Na2SO4), filtered, and concen-
trated under vacuum. The crude product was purified by flash chro-
matography (100 g SiO2, 0–10% EtOAc/hexanes) to yield 6 as a clear
yellow oil (3.51 g, 90%); Rf = 0.70 (50:50).
IR (thin film): 3425, 2976, 2931, 2868, 2096, 1667, 1482, 1451, 1428,
1393, 1365, 1249, 1161, 1134, 876, 792, 771, 706 cm–1. Note: some
peaks are broadened/doubled due to carbamate rotamers.
1H NMR (300 MHz, CDCl3): δ = 7.32–7.30 (m, 1 H), 7.23–7.12 (m, 3 H),
4.63 (t, J = 6.2 Hz, 1 H), 3.75 (m, 2 H), 3.44–3.42 (m, 2 H), 2.83–2.78
(m, 5 H), 2.66–2.51 (br s, 1 H), 1.38 (br s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 155.8, 140.0, 136.8, 129.3, 129.1, 129.0,
127.8, 125.3, 79.5, 67.7, 66.5, 50.8, 50.1, 34.5, 34.0, 28.5.
HRMS (ESI+): m/z [M + Na]+ calcd for C16H24N4O3Na: 343.1746; found:
343.1741.
IR (thin film): 2975, 2930, 1690, 1632, 1602, 1582, 1480, 1451, 1422,
1391, 1364, 1163, 1133, 905, 878, 798, 771, 713 cm–1. Note: some
peaks are broadened/doubled due to carbamate rotamers.
tert-Butyl N-{2-[3-(1-Amino-2-hydroxyethyl)phenyl]ethyl}-
N-methylcarbamate (9)
To a 50 mL round-bottomed flask were added azide 8 (503 mg, 1.57
mmol) and MeOH (100 mL). The headspace was flushed with N2 for 5
min, and Pd/C (167 mg, 0.157 mmol) was added. The flask was sealed
and purged with H2. The reaction mixture was stirred at r.t. for 4 h
under a positive pressure of H2 using a balloon. The mixture was fil-
tered through a Celite plug, and the filtrate was condensed down un-
der vacuum to yield amine 9 as a colorless oil (442 mg, 96%).
1H NMR (300 MHz, CDCl3): δ = 7.33–7.07 (m, 4 H), 6.69 (dd, J = 17.6,
10.9 Hz, 1 H), 5.74 (d, J =17.6 Hz, 1 H), 5.21 (d, J = 10.9 Hz, 1 H), 3.42 (t,
J = 7.0 Hz, 2 H), 2.84–2.79 (m, 5 H), 1.44–1.39 (m, 9 H).
13C NMR (75 MHz, CDCl3): δ = 155.7, 139.6, 137.8, 136.9, 128.7, 128.5,
126.9, 124.3, 113.9, 79.3, 50.9, 35.0, 34.6, 28.4.
HRMS (ESI+): m/z [M + Na]+ calcd for C16H23NO3Na: 284.1626; found:
284.1621.
IR (thin film): 3355, 3297, 2974, 2929, 2865, 1686, 1481, 1451, 1392,
1364, 1305, 1248, 1215, 1162, 1133, 1049, 877, 823, 794, 771, 706
cm–1. Note: some peaks are broadened/doubled due to carbamate ro-
tamers.
tert-Butyl N-Methyl-N-{2-[3-(oxiran-2-yl)phenyl]ethyl}carba-
mate (7)
In a 25 mL oven-dried round-bottomed flask, a solution of olefin 6
(1.03 g, 3.92 mol) in anhyd CH2Cl2 (15 mL) was cooled to 0 °C. While
stirring, mCPBA (1.26 g, 5.11 mmol) was slowly added, and the reac-
tion mixture was stirred for 3 h at 0 °C. The mixture was allowed to
warm to 20 °C and stirred for an additional 16 h. Then the mixture
was diluted with hexanes (200 mL), and the organic layer was washed
with 50% sat. aq NaHCO3 (3 × 50 mL) and brine (50 mL), dried (Na2SO4),
filtered, and concentrated under vacuum to afford a pale yellow oil.
The crude product was purified by flash chromatography (100 g SiO2,
0–20% EtOAc/hexanes) to yield epoxide 7 as a colorless oil (940 mg,
75%); Rf = 0.77 (50:50 EtOAc/hexanes).
1H NMR (300 MHz, CDCl3): δ = 7.30–7.09 (m, 5 H), 4.02 (dd, J = 7.9, 4.4
Hz, 1 H), 3.72 (dd, J = 10.7, 4.4 Hz, 1 H), 3.55 (dd, J = 10.7, 7.9 Hz, 1 H),
3.44–3.41 (m, 2 H), 2.83–2.80 (m, 5 H), 1.38 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 155.8, 143.2, 139.6, 128.9, 128.1, 127.2,
124.5, 79.4, 68.2, 57.4, 50.8, 34.6, 34.1, 28.5.
HRMS (ESI+): m/z [M + H]+ calcd for C16H27N2O3: 295.2022; found:
295.2016.
tert-Butyl N-[2-(3-{2-Hydroxy-1-[(pyridin-2-yl)formamido]eth-
yl}phenyl)ethyl]-N-methylcarbamate (10)
IR (thin film): 2975, 2930, 1687, 1480, 1451, 1391, 1364, 1161, 1132,
879, 792, 771, 702 cm–1. Note: some peaks are broadened/doubled
due to carbamate rotamers.
To an oven-dried 100 mL round-bottomed flask were added amine 9
(450 mg, 1.53 mmol) and anhyd CH2Cl2 (30 mL). Then picolinic acid
(190 mg, 1.53 mmol), HOBt (370 mg, 2.29 mmol), EDC·HCl (440 mg,
2.29 mmol), and DIPEA (523 μL, 3.06 mmol) were sequentially added
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–M