X. Wu et al. / Tetrahedron xxx (2017) 1e8
5
(300 MHz, CDCl3)
d
8.11 (d, J ¼ 13.6 Hz, 1H), 7.90 (d, J ¼ 13.6 Hz, 1H),
2:1) to gain compound 13b (24 mg, 65% yield). 1H-NMR (300 MHz,
CDCl3) 7.46 (s, 1H), 6.63 (s, 1H), 6.56 (broad s, 1H), 3.85 (s, 3H),
3.62e3.52 (m, 2H), 2.77 (t, J ¼ 6.8, 2H), 2.32 (s, 3H).
6.96e6.88 (m, 2H), 6.82e6.74 (m, 1H), 5.33 (broad s, 1H), 3.80 (s,
d
3H). 13C-NMR (75 MHz, MeOD)
118.8, 118.1, 115.9, 56.4.
d
154.4, 153.9, 139.0, 136.8, 121.5,
4.2.12. 2-(2-aminoethyl)-5-chloro-4-methoxyphenol (14a) and 5-
chloro-4-methoxy-2-(2-((2-methoxybenzyl)amino)ethyl)phenol
(15a)
4.2.8. 2-(2-aminoethyl)-4-methoxyphenol (11)
Compound 10 (247 mg, 1.27 mmol) was dissolved in THF (8 mL)
and cooled to 0 ꢀC. LiAlH4 (5.1 mL, 1 M in THF solution) was added
dropwise and the reaction mixture was left to stir under nitrogen
gas flow at 65 ꢀC for 4 h. Cold water was added to the reaction along
with 15% NaOH (aq.) in excess and some additional THF. The so-
lution was vacuum filtered and the filtrate was evaporated in vac-
uum and pre-absorbed on to silica gel before purification using
flash-column chromatography (DCM/MeOH/Et3N 90:10:1) to gain
compound 1120 (150 mg, 71% yield). 1H-NMR (300 MHz, CDCl3)
NaOH (aq.) (40 mL, 0.223 mmol, 5 M) was added to a solution of
compound 13a (38.4 mg, 0.113 mmol) in EtOH (1 mL) and the re-
action mixture was stirred at room temperature overnight. The pH
was adjusted to around 8e9 using 1 N HCl (aq.) and the solution
was extracted using DCM (3 ꢁ 10 mL). The solvent was evaporated
and part of the resulting compound 14a (11.7 mg, 0.0582 mmol)
was re-dissolved in DCE (1 mL). 2-methoxy benzaldehyde (7.7 mL,
0.0640 mmol), sodium cyanoborohydride (7.3 mg, 0.116 mmol) and
one drop of AcOH were added to the solution, which was stirred at
room temperature overnight. The solvent was evaporated in vac-
uum and the crude purified using flash-column chromatography
(DCM/MeOH/Et3N 96:4:1) and preparative LC to gain product 15a
(6.8 mg, 36% yield) as colorless syrupy. 1H-NMR (300 MHz, CDCl3)
d
6.84 (d, J ¼ 8.7 Hz, 1H), 6.67 (dd, J ¼ 8.7, 3.0 Hz, 1H), 6.58 (d,
J ¼ 3 Hz,1H), 3.73 (s, 3H), 3.10e3.03 (m, 2H), 2.80e2.72 (m, 2H). 13C-
NMR (75 MHz, CDCl3)
42.6, 36.2.
d 152.8, 150.6, 128.8, 118.1, 116.7, 113.0, 55.9,
4.2.9. 4-methoxy-2-(2-(2,2,2-trifluoroacetamido)ethyl)phenyl
acetate (12)
d
7.29 (td, J ¼ 7.7, 1.1 Hz,1H), 7.21 (dd, J ¼ 7.7, 1.7 Hz, 1H), 6.98 (s, 1H),
6.96e6.85 (m, 2H), 6.57 (s,1H), 3.90 (s, 2H), 3.86 (s, 3H), 3.81 (s, 3H),
Compound 11 (75.2 mg, 0.45 mmol) was dissolved in THF (1 mL)
2.97e2.87 (m, 2H), 2.85e2.72 (m, 2H). 13C-NMR (75 MHz, CDCl3)
and trifluoroacetic anhydride (125
mL, 0.899 mmol) and Et3N
d 157.7, 151.5, 147.9, 130.8, 129.6, 126.4, 121.5, 120.8, 120.4, 119.4,
(125 L, 0.899 mmol) was added to the solution. The reaction
m
115.6,110.6, 57.2, 55.5, 49.0, 48.9, 33.3. ESI-HRMS positive mode (m/
35
mixture was stirred at room temperature overnight. The solvent
was evaporated in vacuum, water was added to the crude and then
extracted using DCM (3 ꢁ 15 mL). The solvent was once again
evaporated in vacuum and the crude product was re-dissolved in
z): calcd. for C
H
ClNO3 ([MþH]þ): 322.1210. Found: 322.1211;
17 21
37
calcd. for C
H
17 21
ClNO3 ([MþH]þ): 324.1180. Found: 324.1180.
4.2.13. 2-(2-aminoethyl)-5-iodo-4-methoxyphenol (14b) and 5-
iodo-4-methoxy-2-(2-((2-methoxybenzyl)amino)ethyl)phenol
(15b)
CHCl3 (2 mL). Acetyl chloride (47 mL, 0.54 mmol) and Et3N (81 mL,
0.58 mmol) were added to the solution and stirred at room tem-
perature overnight. Saturated NaHCO3 (aq.) was added to the so-
lution and the organic phase was removed and evaporated in
vacuum. The crude was purified using flash-column chromatog-
raphy (n-heptane/EtOAc 2:1) to gain compound 12 (70.6 mg, 51%
NaOH (aq.) (20 mL, 0.111 mmol, 5 M) was added to a solution of
compound 13b (24 mg, 0.0557 mmol) in EtOH (0.5 mL) and water
(0.5 mL) and the reaction mixture was stirred at room temperature
overnight. The pH was adjusted to around 8e9 using 1 N HCl (aq.)
and the solution was extracted using DCM (3 ꢁ 10 mL). The solvent
was evaporated in vacuum and the resulting compound 14b
(15.8 mg, 0.0539 mmol) was re-dissolved in DCE (1 mL). 2-methoxy
yield). 1H-NMR (300 MHz, CDCl3)
d
6.96 (d, J ¼ 8.8 Hz, 1H), 6.80 (dd,
J ¼ 8.8, 3.0 Hz,1H), 6.74 (d, J ¼ 3.0 Hz,1H), 6.66 (broad s,1H), 3.78 (s,
3H), 3.62e3.50 (m, 2H), 2.77 (t, J ¼ 6.9 Hz, 2H), 2.32 (s, 3H). 13C-
NMR (75 MHz, CDCl3)
d
170.5, 157.8, 142.8, 130.9, 123.6, 115.9 (q,
benzaldehyde (7.2 mL, 0.0593 mmol), sodium cyanoborohydride
JCF ¼ 284.1 Hz, CF3), 115.5, 113.6, 55.7, 40.3, 29.4, 20.9.
(6.8 mg, 0.108 mmol) and one drop of AcOH were added to the
solution that was left to stir at room temperature for about 2 h. The
solvent was evaporated in vacuum and the crude purified using
flash-column chromatography (DCM/MeOH/Et3N 98:2:1) and pre-
parative LC to gain product 15b (5.8 mg, 25% yield) as pale yellow
4.2.10. 5-chloro-4-methoxy-2-(2-(2,2,2-trifluoroacetamido)ethyl)
phenyl acetate (13a)
Compound 12 (53.3 mg, 0.175 mmol) was dissolved in ACN
(1 mL) and NCS (25.7 mg, 0.192 mmol) was added at 0 ꢀC. The re-
action mixture was then left to reach room temperature and stirred
overnight. The solvent was evaporated in vacuum and the crude
was purified using flash-column chromatography (n-heptane/
EtOAc 2:1) to gain compound 13a (38.4 mg, 65% yield). 1H-NMR
syrupy. 1H-NMR (300 MHz, CDCl3)
d 7.32e7.28 (m, 2H), 7.18 (dd,
J ¼ 7.4, 1.7 Hz, 1H), 6.96e6.86 (m, 2H), 6.48 (s, 1H), 3.85 (s, 5H), 3.78
(s, 3H), 2.91e2.82 (m, 2H), 2.79e2.71 (m, 2H). 13C-NMR (75 MHz,
CDCl3)
d 157.9, 152.4, 151.3, 130.7, 129.4, 128.7, 128.2, 125.8, 120.8,
114.1, 110.5, 84.1, 57.4, 55.4, 49.1, 49.0, 34.2. ESI-HRMS positive
mode (m/z): calcd. for C17H21INO3 ([MþH]þ): 414.0566. Found:
414.0569.
(300 MHz, CDCl3)
d 7.10 (s, 1H), 6.74 (s, 1H), 6.60 (broad s, 1H), 3.87
(s, 3H), 3.61e3.50 (m, 2H), 2.78 (t, J ¼ 6.9 Hz, 2H), 2.32 (s, 3H). 13C-
NMR (75 MHz, CDCl3)
d 170.0, 153.4, 142.3, 129.2, 124.5, 121.6, 115.7
(q, JCF ¼ 284.7 Hz, CF3), 113.0, 56.5, 39.9, 29.1, 20.7.
4.2.14. Tert-butyl 2,5-dimethoxyphenethylcarbamate (17)
A
mixture of 3-(2,3-dimethoxyphenyl) propionic acid 16
4.2.11. 5-iodo-4-methoxy-2-(2-(2,2,2-trifluoroacetamido)ethyl)
phenyl acetate (13b)
(200 mg, 0.950 mmol), sodium azide (216 mg, 3.33 mmol), tetra-
butylammonium bromide (45.6 mg, 0.143 mmol), zinc triflate
N-iodosuccinimide (24.2 mg, 0.108 mmol) was added to a so-
lution of compound 12 (26.4 mg, 0.086 mmol) in AcOH (1 mL) and.
After 4 h, the conversion was about 50% according to LC-MS.
Additional N-iodosuccinimide (9.70 mg, 0.043 mmol) was added
(11.4 mg, 31.4 mmol) and di-tert-butyldicarbonate (228 mg,
1.05 mmol) in dry THF (9.5 mL) was stirred at 40 ꢀC under nitrogen
overnight. When the reaction was completed according to LC-MS, a
10% NaNO2 aq. solution (6 mL) was added along with EtOAc (6 mL)
and the reaction mixture was left stir at room temperature for
20 min. The water phase was extracted using additional EtOAc
(3 ꢁ 6 mL) and the organic phases were combined and washed with
saturated aq. NH4Cl (6 mL), saturated Na2SO4 (6 mL) and saturated
NaHCO3 (6 mL). The solvent was evaporated in vacuum and the
along with H2SO4 (2.4
mL, 18 M, 0.043 mmol) and the reaction
mixture was stirred overnight. An excess of Na2S2O3 (aq.) and Et2O
was added to the reaction mixture and the water phase was
removed. The solvent was evaporated in vacuum and the crude
purified using flash-column chromatography (n-heptane/EtOAc
Please cite this article in press as: Wu X, et al., Synthesis and identification of metabolite biomarkers of 25C-NBOMe and 25I-NBOMe,