The Journal of Organic Chemistry
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1H), 7.24 (t, J = 7.8 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 3.81 (s, 3H).
13C NMR (CDCl3, 100 MHz): δ 159.8, 153.2, 152.1, 139.7, 134.0,
133.1, 130.7, 130.6, 129.1, 125.5, 124.7, 123.6, 123.0, 115.0, 114.0,
94.6, 90.4, 87.3, 55.3. HRMS-ESI: C21H15IN2O [M·H]+ calcd
439.0307, found 439.0318. Melting point: 116 °C.
was dried with MgSO4, filtered, and concentrated in vacuo. The crude
mixture was purified by column chromatography on neutral alumina
with CH2Cl2/MeOH = 98:2. The resulting colorless waxy solid was
dissolved in CH2Cl2 (20 mL), to which was added trifluoroacetic acid
(6 mL). The reaction mixture was stirred for 3 h, neutralized with
concentrated Na2CO3 solution, extracted with CH2Cl2 (×5), dried
with MgSO4, filtered, and concentrated in vacuo to yield a yellow
viscous oil product (1.56 g, 7.28 mmol, 84% yield). 1H NMR (CDCl3,
400 MHz): δ 7.33 (s, 1H), 3.38 (br, 1H), 3.23 (m, 2H), 1.72 (m, 3H),
1.50 (m, 4H), 1.30 (m, 6H), 0.95 (m, 6H), 0.89 (m, 3H). 13C NMR
(CDCl3, 100 MHz): δ 175.3, 53.4, 44.1, 38.9, 31.3, 29.5, 26.5, 24.7,
23.3, 22.4, 21.2, 13.8. HRMS-ESI: C12H26N2O [M·H]+ calcd 215.2123,
found 215.2124.
3-Ethynyl-3′-(4-methoxyphenylethynyl)azobenzene (11). To
a degassed solution of 10 (200 mg, 0.456 mmol) and DIPA (138 mg,
1.37 mmol) in THF (30 mL) were added PdCl2(PPh3)2 (3 mg, 0.005
mmol), CuI (9 mg, 0.05 mmol), and TMSA (67 mg, 0.68 mmol), and
the solution was stirred under Ar for 20 min. The reaction mixture was
concentrated under vacuum and purified by column chromatography
on silica gel with hexanes/CH2Cl2 = 9:1 to 7:3. The resulting orange
solid product was dissolved in THF (5 mL) and MeOH (5 mL), to
which was added 1 mL of saturated K2CO3 (in MeOH). The solution
was stirred for 1 h. The solvent was evaporated, and the residue was
filtered through a short pad of silica gel with CH2Cl2, yielding an
L-Leucine-n-hexylamide-N-carbonyl-4-iodobenzene (15). p-
Iodobenzoic acid (1.34 g, 5.39 mmol) was dissolved in SOCl2 (10
mL), and the solution was refluxed for 1 h. Excess SOCl2 was removed
in vacuo, and the resulting solid was dissolved in CH2Cl2 (30 mL) and
TEA (3 mL). 14 (1.1 g, 5.1 mmol) was added dropwise under ice-bath
conditions, and the resulting solution was warmed to rt and then
stirred for 1 h. The reaction mixture was extracted with CH2Cl2 and
washed with 3 M HCl aqueous solution. The organic phase was dried
with MgSO4, filtered, and concentrated in vacuo to produce a white
1
orange solid product (130 mg, 0.386 mmol, 85% yield). H NMR
(CDCl3, 400 MHz): δ 8.06 (s, 2H), 7.91 (d, J = 7.8 Hz, 1H), 7.87 (d, J
= 7.8 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.49
(m, 4H), 6.89 (d, J = 8.6 Hz, 2H), 3.82 (s, 3H), 3.14 (s, 1H). 13C
NMR (CDCl3, 100 MHz): δ 159.8, 152.3, 152.2, 134.5, 133.9, 133.2,
129.12, 129.10, 126.4, 125.5, 124.7, 123.6, 123.2, 122.9, 115.0, 114.0,
90.3, 87.3, 82.8, 78.0, 55.3. HRMS-ESI: C23H16N2O [M·H]+ calcd
337.1341, found 337.1335. Melting point: 113 °C.
1
solid (2.3 g, 5.1 mmol, quantitative yield). H NMR (CDCl3, 400
MHz): δ 7.73 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.15 (d, J =
7.8 Hz, 1H), 6.59 (s, 1H), 4.67 (m, 1H), 3.26−3.10 (m, 2H), 1.73 (m,
3H), 1.46 (m, 2H), 1.26 (s, 6H), 0.96 (s, 6H), 0.86 (m, 3H). 13C
NMR (CDCl3, 100 MHz): δ 172.0, 166.6, 137.6, 133.2, 128.8, 98.7,
52.4, 41.3, 39.6, 31.4, 29.3, 26.5, 24.9, 22.8, 22.5, 22.4, 14.0. HRMS-
ESI: C19H29IN2O2 [M·Na]+ calcd 467.1172, found 467.1190. Melting
point: 134 °C.
F2 Azido Side Arm (12). To a degassed solution of 11 (180 mg,
0.535 mmol), 6 (1.8 g, 5.14 mmol), and DBU (244 mg, 1.61 mmol) in
toluene was added CuI (31 mg, 0.16 mmol), and the solution was
stirred at 70 °C for 30 min under argon. The reaction mixture was
concentrated in vacuo and purified by column chromatography on
silica gel with CH2Cl2/acetone = 95:5, producing an orange viscous oil
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(255 mg, 0.371 mmol, 69% yield). H NMR (CDCl3, 400 MHz): δ
L-Leucine-n-hexylamide-N-carbonyl-4-ethynylbenzene (16).
To a degassed solution of 15 (1.5 g, 3.38 mmol) and DIPA (182 mg,
1.8 mmol) in THF (50 mL) were added PdCl2(PPh3)2 (48 mg, 0.068
mmol), CuI (64 mg, 0.34 mmol), and TMSA (432 mg, 4.39 mmol),
and the solution was stirred under argon for 1 h. The reaction mixture
was filtered through a pad of Celite and concentrated in vacuo. The
resulting crude mixture was purified by column chromatography on
silica gel with CH2Cl2/MeOH = 95:5. The resulting brownish oil
product was dissolved in THF (30 mL) and MeOH (30 mL), to which
was added 5 mL of saturated K2CO3 (in MeOH). The mixture was
stirred for 2 h, concentrated in vacuo, and filtered through a short pad
of silica gel with CH2Cl2/MeOH = 95:5 solution to provide a slightly
8.45 (s, 1H), 8.43 (s, 1H), 8.19 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 8.12
(s, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.83 (s,
1H), 7.81 (s, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H),
7.52 (m, 3H), 6.91 (d, J = 8.6 Hz, 2H), 4.57 (t, J = 5.0 Hz, 2H), 3.89
(t, J = 5.0 Hz, 2H), 3.85 (s, 3H), 3.75−3.65 (m, 4H), 3.66 (m, 2H),
3.53 (t, J = 5.0 Hz, 2H), 3.34 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ
164.4, 169.7, 152.7, 152.2, 147.9, 142.5, 138.0, 133.7, 133.2, 133.1,
131.8, 129.7, 129.0, 128.3, 125.4, 124.6, 123.6, 122.7, 119.7, 119.6,
117.9, 116.7, 114.92, 114.86, 114.0, 90.2, 87.3, 71.8, 70.61, 70.55, 70.5,
68.9, 64.9, 58.9, 55.2. HRMS-ESI: C37H34N8O6 [M·H]+ calcd
687.2680, found 687.2682.
Foldamer F2. To a degassed solution of 4 (50 mg, 0.12 mmol), 12
(164 mg, 0.24 mmol), and DBU (71 mg, 0.47 mmol) was added CuI
(7 mg, 0.04 mmol), and the solution was stirred at 70 °C for 30 min.
The reaction mixture was concentrated in vacuo and purified by
column chromatography on silica gel with CH2Cl2/MeOH = 95:5 to
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brown solid (1.08 g, 3.15 mmol, 93% yield). H NMR (CDCl3, 400
MHz): δ 7.75 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.07 (d, J =
7.8 Hz, 1H), 6.55 (s, 1H), 4.69 (m, 1H), 3.31−3.12 (m, 2H), 3.20 (s,
1H), 1.74 (m, 3H), 1.48 (m, 2H), 1.26 (s, 6H), 0.98 (m, 6H), 0.86 (m,
3H). 13C NMR (CDCl3, 100 MHz): δ 172.5, 168.6, 133.7, 131.9,
127.2, 125.3, 82.7, 79.4, 52.6, 41.2, 39.5, 21.4, 29.3, 26.5, 24.9, 22.8,
22.5, 22.3, 13.9. HRMS-ESI: C21H30N2O2 [M·Na]+ calcd 365.2205,
found 365.2216. Melting point: 107 °C.
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produce an orange viscous oil (167 mg, 0.093 mmol, 79% yield). H
NMR (5 mM in CD2Cl2 with 10 equiv of TBACl, 500 MHz): δ 10.86
(s, 2H), 10.34 (s, 2H), 9.29 (s, 1H), 9.13 (s, 2H), 8.70 (s, 2H), 8.54 (s,
2H), 8.38 (s, 2H), 8.29 (s, 2H), 7.82 (s, 2H), 7.75 (d, J = 7.3 Hz, 2H),
7.68 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H), 7.57 (br, 1H), 7.40
(t, J = 6.6 Hz, 1H), 7.35 (t, J = 7.7 Hz, 2H), 7.33 (d, J = 8.8 Hz, 4H),
7.25 (t, J = 7.7 Hz, 2H), 7.22 (t, J = 7.7 Hz, 2H), 6.83 (d, J = 8.8 Hz,
4H), 4.76 (m, 1H), 4.57 (t, J = 4.8 Hz, 4H), 3.91 (t, J = 4.8 Hz, 4H),
3.82 (s, 6H), 3.74 (m, 4H), 3.68 (m, 4H), 3.60 (m, 8H), 3.56 (m, 4H),
3.51−3.46 (m, 8H), 3.33 (s, 3H), a methoxy peak (3H) overlaps with
a TBA peak, 1.85 (m, 3H), two methyl groups overlap with a TBA
peak. 13C NMR (CD2Cl2, 125 MHz): δ 173.0, 167.1, 165.1, 160.4,
152.7, 152.4, 148.4, 148.2, 138.6, 138.5, 136.4, 133.8, 133.7, 133.5,
132.1, 131.8, 129.6, 129.4, 128.5, 128.3, 126.3, 124.9, 123.4, 122.9,
122.8, 122.5, 121.2, 120.7, 119.0, 118.8, 115.3, 114.5, 114.2, 90.7, 87.7,
72.4, 71.3, 71.03, 70.98, 70.84, 70.76, 70.1, 69.5, 59.1, (some Tg signals
overlap) 55.9, 42.2, 39.8, 30.2, 25.6, 23.4, 22.4. HRMS-ESI:
C98H100N18O17 [M·Cl]− calcd 1835.7202, found 1835.7235.
3-(4-(L-Leucine-n-hexylamide-N-carbonyl)phenylethynyl)-
3′-iodoazobenzene (17). To a degassed solution of 16 (631 mg,
1.84 mmol), 3,3′-diiodoazobenzene (4 g, 9.22 mmol), and DIPA (745
mg, 7.36 mmol) in THF (100 mL) were added PdCl2(PPh3)2 (26 mg,
0.037 mmol) and CuI (35 mg, 0.18 mmol), and the solution was
stirred under argon for 1 h. The reaction mixture was concentrated in
vacuo and purified by column chromatography on silica gel with
CH2Cl2/acetone = 95:5 to provide an orange waxy solid product (790
1
mg, 1.22 mmol, 66% yield). H NMR (CDCl3, 500 MHz): δ 8.25 (s,
1H), 8.07 (s, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H),
7.80 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 7.8 Hz,
1H), 7.60 (d, J = 8.3 Hz, 2H), 7.50 (t, J = 8.3 Hz, 1H), 7.26 (t, J = 8.3
Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.20 (t, J = 4.9 Hz, 1H), 4.64 (m,
1H), 3.27 (m, 2H), 1.83−1.69 (m, 3H), 1.52 (m, 2H), 1.30 (m, 6H),
1.01 (s, 3H), 1.00 (s, 3H), 0.89 (t, J = 6.8 Hz, 3H). 13C NMR (CDCl3,
125 MHz): δ 171.8, 166.6, 153.4, 152.3, 139.9, 134.2, 133.6, 131.8,
130.9, 130.6, 129.3, 127.2, 126.6, 125.9, 124.0, 123.7, 123.5, 94.5, 91.0,
89.4, 52.4, 41.6, 39.7, 31.4, 29.5, 26.5, 25.1, 22.9, 22.50, 22.48, 13.9 (a
single peak is missing, presumably because of overlap in the aromatic
L-Leucine-n-hexylamide (14). To a solution of Boc-L-leucine (2
g, 8.65 mmol), DEPBT (2.85 g, 9.52 mmol), and TEA (1.14 g, 11.3
mmol) in THF (50 mL) was added n-hexylamine (1.14 g, 11.3 mmol),
and the mixture was stirred overnight. The reaction mixture was
extracted with ether (×3) and washed with water. The organic phase
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dx.doi.org/10.1021/jo501595k | J. Org. Chem. 2014, 79, 8383−8396