ACS Chemical Neuroscience
Research Article
2-(2-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-oxoethoxy)ethan-1-
aminium Trifluoroacetate (23). See Procedures G and Ha: 94 mg
(0.43 mmol) of 2-(2-((tert-butoxycarbonyl)amino)ethoxy)acetic acid,
223 mg (0.43 mmol, 1.0 equiv) of PyBOP, 60 μL (63 mg, 0.47 mmol,
1.1 equiv) of 1,2,3,4-tetrahydroisoquinoline, 470 μL (432 mg, 4.3
mmol, 10 equiv) of NMM, and 4 mL of DMF. The intermediate was
purified by column chromatography (0−5% MeOH in DCM) and used
without further purification. Procedure Ha: 5 mL of dioxane and 0.5 of
mL conc. HCl were added, and the solution was concentrated in vacuo
after 5 min. Compound 23 (121 mg, yield = 81%) was isolated as a
colorless oil. 1H NMR (400 MHz, methanol-d4) δ 7.21−7.12 (m, 4H),
4.69 (s, 1H), 4.55 (s, 1H), 4.43 (s, 1H), 4.42 (s, 1H), 3.82−3.74 (m,
3H), 3.59 (t, J = 6.0 Hz, 1H), 3.15 (q, J = 4.5 Hz, 2H), 2.91 (t, J = 6.0
Hz, 1H), 2.85 (t, J = 6.0 Hz, 1H). 13C NMR (101 MHz, methanol-d4) δ
169.39, 169.35, 161.16, 160.80, 160.44, 160.08, 134.54, 134.14, 132.52,
131.97, 128.26, 127.98, 126.70, 126.50, 126.26, 126.15, 126.03, 125.87,
120.64, 117.75, 114.86, 68.20, 45.19, 43.79, 41.68, 39.89, 39.22, 28.46,
27.74.
4-(2-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)piperidin-1-
ium Hydrochloride (24). See Procedures G and Ha: 75 mg (0.31
mmol) of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid, 161 mg
(0.31 mmol, 1.0 equiv) of PyBOP, 40 μL (42 mg, 0.32 mmol, 1.0 equiv)
of 1,2,3,4-tetrahydroisoquinoline, 340 μL (313 mg, 3.1 mmol, 10 equiv)
of NMM, and 4 mL of DMF. The intermediate was purified by column
chromatography (0−5% MeOH in DCM) and used without further
purification. Procedure Ha: 5 mL of dioxane and 0.5 mL of conc. HCl
were, added and the solution was concentrated in vacuo after 1 min.
Compound 24 (86 mg, yield = 95%) was isolated as an off white
amorphous solid. 1H NMR (500 MHz, methanol-d4) δ 7.22−7.11 (m,
4H), 4.70 (s, 1H), 4.68 (s, 1H), 3.78 (t, J = 6.0 Hz, 1H), 3.75 (t, J = 5.9
Hz, 1H), 3.37 (ddd, J = 12.8, 6.3, 3.1 Hz, 2H), 3.05−2.94 (m, 2H), 2.92
(t, J = 5.9 Hz, 1H), 2.84 (t, J = 6.0 Hz, 1H), 2.49 (t, J = 7.3 Hz, 2H), 2.14
(ddtt, J = 14.4, 10.7, 6.9, 3.8 Hz, 1H), 2.05−1.95 (m, 2H), 1.55−1.41
(m, 2H). 13C NMR (126 MHz, methanol-d4) δ 170.84, 170.78, 160.78,
160.49, 134.67, 134.24, 132.94, 132.62, 128.26, 127.99, 126.62, 126.38,
126.19, 126.08, 126.03, 125.80, 117.46, 115.14, 43.92, 43.73, 43.71,
43.26, 39.96, 38.72, 38.52, 30.66, 30.63, 28.87, 28.46, 28.42, 27.92.
1-(2-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)piperazine-
1,4-diium Trifluoroacetate (25). See Procedures G and Ha: 78 mg
(0.32 mmol) of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)acetic acid,
172 mg (0.33 mmol, 1.0 equiv) of PyBOP, 50 μL (53 mg, 0.39 mmol,
1.2 equiv) of 1,2,3,4-tetrahydroisoquinoline, 350 μL (322 mg, 3.2
mmol, 10 equiv) of NMM, and 4 mL of DMF. The intermediate was
purified by column chromatography (0−5% MeOH in DCM) and used
without further purification. Procedure Ha: 5 mL of dioxane and 0.5 mL
conc. HCl were added and the solution was concentrated in vacuo after
5 min. Compound 25 (156 mg, quantitative yield) was isolated as a
white waxy solid. 1H NMR (500 MHz, methanol-d4) δ 7.25−7.09 (m,
4H), 4.70 (s, 1H), 4.63 (s, 1H), 4.40 (s, 2H), 3.79 (t, J = 6.1 Hz, 1H),
3.69−3.57 (m, 9H), 2.96 (t, J = 6.0 Hz, 1H), 2.87 (t, J = 6.1 Hz, 1H).
13C NMR (126 MHz, methanol-d4) δ 163.34, 163.26, 161.82, 161.54,
119.71, 117.40, 115.09, 112.77, 49.10, 49.00, 45.56, 43.93, 42.14, 40.08,
32.25, 28.34, 27.67.
tert-Butyl (2-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-
(methyl)carbamate (27). See Procedure G: 99 mg (0.52 mmol) of
N-(tert-butoxycarbonyl)-N-methylglycine, 271 mg (0.52 mmol, 1.0
equiv) of PyBOP, 70 μL (74 mg, 0.55 mmol, 1.1 equiv) of 1,2,3,4-
tetrahydroisoquinoline, 580 μL (534 mg, 5.3 mmol, 10 equiv) of NMM,
and 4 mL of DMF. The product was purified by column
chromatography (0−50% EtOAc in hexanes), yielding compound 27
(152 mg, yield = 95%) as a colorless oil. 1H NMR (500 MHz,
chloroform-d) δ 7.22−7.02 (m, 4H), 4.71 (d, J = 9.6 Hz, 1H), 4.57 (s,
1H), 4.13 (d, J = 6.2 Hz, 1H), 4.05 (s, 1H), 3.84−3.77 (m, 1H), 3.67−
3.59 (m, 1H), 2.92 (d, J = 5.4 Hz, 3H), 2.85 (dt, J = 15.7, 5.5 Hz, 2H),
1.46 (s, 6H), 1.39 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ
167.55, 167.46, 156.22, 134.87, 133.97, 133.23, 132.16, 129.01, 128.85,
128.28, 126.94, 126.62, 126.57, 126.36, 126.07, 125.96, 79.95, 51.02,
50.56, 50.44, 46.29, 44.36, 42.43, 39.93, 35.46, 29.30, 28.36, 28.29.
tert-Butyl (2-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-
carbamate (28). See Procedure G: 91 mg (0.52 mmol) of (tert-
butoxycarbonyl)glycine, 270 mg (0.52 mmol, 1.0 equiv) of PyBOP, 70
μL (74 mg, 0.55 mmol, 1.1 equiv) of 1,2,3,4-tetrahydroisoquinoline,
570 μL (524 mg, 5.2 mmol, 10 equiv) of NMM, and 4 mL of DMF. The
product was purified by column chromatography (0−66% EtOAc in
hexanes), yielding compound 28 (136 mg, yield = 90%) as a yellow oil.
1H NMR (500 MHz, chloroform-d) δ 7.22−7.03 (m, 4H), 5.59 (s, 1H),
4.71 (s, 1H), 4.52 (s, 1H), 4.02 (dd, J = 8.5, 4.4 Hz, 2H), 3.81 (t, J = 6.0
Hz, 1H), 3.58 (t, J = 5.9 Hz, 1H), 2.86 (dt, J = 22.9, 6.0 Hz, 2H), 1.43 (s,
9H). 13C NMR (126 MHz, chloroform-d) δ 167.29, 155.83, 134.70,
133.80, 132.83, 131.68, 128.84, 128.30, 127.12, 126.75, 126.70, 126.55,
126.53, 126.11, 79.61, 45.93, 44.38, 42.64, 42.48, 42.03, 40.06, 29.09,
28.34, 28.29.
tert-Butyl (2-(3,4-Dihydroisoquinolin-2(1H)-yl)ethyl)(methyl)-
carbamate (29). See Procedure E: 48 mg (0.16 mmol) of 27, 550
μL (1.1 mmol, 7.0 equiv) of 2 M BH3*Me2S in THF, and 4 mL THF.
The concentrated product was purified by column chromatography
(0−33% EtOAc in hexanes), yielding compound 29 (30 mg, yield =
66%) as a colorless oil. 1H NMR (500 MHz, chloroform-d) δ 7.26−7.13
(m, 3H), 7.02 (d, J = 7.1 Hz, 1H), 4.23 (d, J = 15.6 Hz, 1H), 3.96−3.58
(m, 3H), 3.35−2.78 (m, 9H), 1.40 (s, 4H), 1.34 (s, 5H). 13C NMR
(126 MHz, chloroform-d) δ 129.75, 128.59, 127.60, 127.36, 127.00,
126.78, 80.00, 79.82, 62.10, 61.03, 54.96, 54.79, 54.10, 53.87, 44.29,
43.94, 35.01, 34.70, 28.32, 24.04.
2-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-oxoethan-1-aminium Tri-
fluoroacetate (30). Procedure Ha: 54 mg (0.19 mmol) of 28, 5 mL
of dioxane and 0.5 mL of conc. HCl were added, and the solution was
concentrated in vacuo after 5 min. Compound 30 (32 mg, yield = 57%)
was isolated as a pinkish white solid. 1H NMR (500 MHz, methanol-d4)
δ 7.24−7.10 (m, 4H), 4.69 (s, 1H), 4.60 (s, 1H), 4.04 (s, 1H), 4.03 (s,
1H), 3.78 (t, J = 6.1 Hz, 1H), 3.64 (t, J = 6.0 Hz, 1H), 2.94 (t, J = 6.0 Hz,
1H), 2.86 (t, J = 6.1 Hz, 1H). 13C NMR (126 MHz, methanol-d4) δ
164.95, 164.90, 161.74, 161.46, 161.18, 160.89, 134.48, 134.04, 132.13,
131.57, 128.28, 128.07, 126.91, 126.69, 126.40, 126.32, 126.08, 125.98,
119.96, 117.64, 115.32, 113.00, 45.64, 44.15, 42.23, 40.39, 28.33, 27.66.
2-((2-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)(methyl)-
amino)-2-oxoethan-1-aminium Trifluoroacetate (31). See Proce-
dures G and Ha: 47 mg (0.15 mmol) of 26, 80 mg (0.15 mmol, 1.0
equiv) of PyBOP, 29 mg (0.17 mmol, 1.1 equiv) of N-(tert-
butoxycarbonyl)glycine, 170 μL (156 mg, 1.5 mmol, 10 equiv) of
NMM, and 4 mL of DMF. The intermediate was purified by column
chromatography (0−5% MeOH in DCM). Procedure Ha: 5 mL of
dioxane and 0.5 mL conc. of HCl were added, and the solution was
concentrated in vacuo after 5 min. Compound 31 (24 mg, yield = 43%)
161.25, 134.44, 134.05, 132.07, 131.59, 128.26, 128.05, 126.90, 126.70,
126.39, 126.31, 126.07, 125.99, 117.61, 115.29, 57.02, 56.93, 49.41,
49.38, 45.84, 44.05, 42.45, 40.69, 40.31, 28.35, 27.64.
2-(3,4-Dihydroisoquinolin-2(1H)-yl)-N-methyl-2-oxoethan-1-
aminium Trifluoroacetate (26). See Procedures G and Ha: 104 mg
(0.55 mmol) of N-(tert-butoxycarbonyl)-N-methylglycine, 288 mg
(0.55 mmol, 1.0 equiv) of PyBOP, 70 μL (74 mg, 0.55 mmol, 1.0 equiv)
of 1,2,3,4-tetrahydroisoquinoline, 600 μL (552 mg, 5.5 mmol, 10 equiv)
of NMM, and 4 mL of DMF. The intermediate was purified by column
chromatography (0−5% MeOH in DCM) and used without further
purification. Procedure Ha: 6 mL of dioxane and 0.6 mL of conc. HCl
were added, and the solution was concentrated in vacuo after 5 min.
Compound 26 (132 mg, yield = 75%) was isolated as a colorless oil that
1
was isolated as a colorless oil. H NMR (500 MHz, methanol-d4) δ
1
7.23−7.12 (m, 4H), 4.71−4.66 (m, 2H), 4.45−4.40 (m, 2H), 4.00 (s,
2H), 3.79 (q, J = 6.0, 5.6 Hz, 1H), 3.71 (td, J = 6.0, 1.8 Hz, 1H), 3.11−
3.02 (m, 3H), 2.98−2.96 (m, 1H), 2.90−2.81 (m, 1H). 13C NMR (126
MHz, Methanol-d4) δ 167.14, 166.71, 160.08, 159.78, 134.59, 134.22,
133.52, 132.63, 128.81, 128.23, 127.97, 127.93, 127.26, 126.68, 126.58,
126.50, 126.30, 126.24, 126.15, 126.00, 125.89, 117.07, 114.76, 55.11,
turned purple overtime. H NMR (500 MHz, methanol-d4) δ 7.23−
7.10 (m, 4H), 4.69 (s, 1H), 4.60 (s, 1H), 4.16 (s, 1H), 4.15 (s, 1H), 3.79
(t, J = 6.1 Hz, 1H), 3.63 (t, J = 6.0 Hz, 1H), 2.94 (t, J = 6.0 Hz, 1H), 2.85
(t, J = 6.0 Hz, 1H), 2.78 (s, 3H). 13C NMR (126 MHz, methanol-d4) δ
164.05, 164.01, 161.03, 160.74, 160.46, 160.16, 134.42, 134.00, 132.18,
131.60, 128.27, 128.05, 126.81, 126.61, 126.33, 126.24, 126.02, 125.92,
N
ACS Chem. Neurosci. XXXX, XXX, XXX−XXX