Page 7 of 10
The Journal of Organic Chemistry
Na2S2O3 solution and brine. After drying over Na2SO4, the solvent
(0.10 mL, 0.57 mmol). The product was further purified by silica
1
2
3
4
5
6
7
8
was removed in vacuo, and the crude product was purified by
repeated silica gel column chromatography (100% hexanes, Rf =
0.50) to yield a white solid (97 mg, 52% yield). 5,6,17,18-
Tetrabromo[3.3]paracyclophane was isolated as a less polar side
product (Rf = 0.45). 1H NMR (500 MHz, chloroform-d): 7.29 (s,
4H), 2.99 (dt, J = 14.4, 6.0 Hz, 4H), 2.58 (dt, J = 14.4, 6.4 Hz, 4H),
2.19 (p, J = 6.1 Hz, 4H). 13C{1H} NMR (125 MHz, chloroform-d):
139.4, 133.5, 124.4, 34.6, 23.9. HRMS (DART) m/z: [M]+ calc’d
for C18H16Br4: 551.7940, found 551.7946. ( ± )-7 could be
synthesized following the same procedure from (±)-6 with a slight
improvement in yield.
gel chromatography (70–90% ethyl acetate in hexanes) and was
obtained as a white solid (10 mg, 41% yield). Crystallization by
slow evaporation from MeOH or EtOH, or by slow cooling from
DMF/H2O, yielded thin needles of insufficient quality for single-
crystal X-ray diffraction. 1H NMR (500 MHz, chloroform-d):
7.68 (br s, 4H), 6.98 (s, 4H), 3.41 (m, 8H), 3.11 (br s, 4H), 2.52 (br
s, 4H), 1.93 (p, J = 5.7 Hz, 4H), 1.71 (m, 4H), 1.03 (t, J = 7.3 Hz,
4H). 13C{1H} NMR (125 MHz, CDCl3): 170.2, 137.2, 136.8,
129.4, 41.7, 29.7 27.8, 22.7, 11.7. HRMS (DART) m/z: [M+H]+
calc’d for C34H49N4O4: 577.3754, found 577.3772.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(±)-5,8,14,17-Tetrabenzylamide[3.3]paracyclophane
((±)-1c).
Synthesized in the same way as (±)-1a using (±)-8 (67 mg, 0.16
mmol), oxalyl chloride (0.20 mL, 2.7 mmol), benzylamine (0.50
mL, 4.6 mmol), and N,N-diisopropylethylamine (DIPEA) (0.10
mL, 0.57 mmol). The product was further purified by silica gel
chromatography (70% ethyl acetate in hexanes) and was obtained
as a white solid (29 mg, 23% yield). Crystallization by slow
evaporation from ethyl acetate/ethanol furnished colorless crystals
(±)-5,8,14,17-Tetracarboxy[3.3]paracyclophane
((±)-8).
Compound (±)-7 (125 mg, 0.226 mmol) was placed in a flame-
dried 2-neck round bottom flask under argon atmosphere and
dissolved in THF (3 mL). The solution was cooled to –78 °C with
a dry ice–acetone bath and a 1.7 M solution of t-butyllithium in
pentane (1.60 mL, 2.71 mmol) was added slowly to the reaction
mixture. The reaction mixture was stirred for 20 min, then CO2 (16
g, 0.36 mol) was bubbled through the solution via a long needle
with stirring until all the gas was consumed. The reaction mixture
warmed to rt and dissolved in 10% NaHCO3 and then acidified with
concentrated HCl. A white precipitate was collected through
filtration and the mother liquor was extracted with ethyl acetate.
The organic layer was separated, dried with Na2SO4, and the
solvent was removed under reduced pressure. The white
precipitate was dissolved in ethyl acetate and the ethyl acetate
solutions were combined and evaporated onto celite. The product
could be further purified with column chromatography on silica gel
(gradient of 90% hexanes:10% isopropanol with 1% trifluoroacetic
acid to 85% hexanes:15% isopropanol with 1% trifluoroacetic acid)
(Rf = 0.1) to yield (±)-8 as a white solid (83 mg, 87% yield) 1H
NMR (500 MHz, acetone-d6): 12.88 (br, 4H), 7.37 (s, 4H), 3.59
(dt, J = 14.1, 6.1 Hz, 4H), 2.54 (dt, J = 14.1, 6.0 Hz, 4H), 2.06 (p,
J = 6.1 Hz, 4H). 13C{1H} NMR (125 MHz, acetone) δ 168.8, 141.3,
134.0, 133.9, 33.1, 29.1. HRMS (DART) m/z: [M-H]- calc’d for
C22H19O8: 411.1085, found 411.1074.
1
suitable for single-crystal X-ray diffraction. H NMR (500 MHz,
chloroform-d) δ 7.99 (br s, 4H), 7.42–7.22 (m, 5H), 6.89 (s, 4H),
4.67–4.49 (m, 8H), 3.00 (br s, 4H), 2.37 (br s, 4H), 1.73 (br s, 4H).
13C{1H} NMR (125 MHz, CDCl3): 170.0, 138.8, 136.8, 136.7,
129.2, 128.6, 128.4, 127.4, 44.0, 33.0, 27.7. HRMS (ESI) m/z:
[M+H]+ calc’d for C50H49N4O4: 769.3748, found: 769.3746.
(±)-5,8,14,17-Tetraphenylamide[3.3]paracyclophane
((±)-1d).
Synthesized in the same way as (±)-1a using (±)-8 (25 mg, 0.060
mmol), oxalyl chloride (0.05 mL, 0.68 mmol), aniline (1.0 mL, 10
mmol), and N,N-diisopropylethylamine (DIPEA) (0.10 mL, 0.57
mmol).
The product was further purified by silica gel
chromatography (0–10% methanol in DCM) and was obtained as
an off-white solid (13 mg, 23% yield). Further purification by
1
recrystallization from ethyl acetate-ethanol yielded pure (±)-1d. H
NMR (500 MHz, chloroform-d) δ 10.57 (br s, 4H), 8.00–7.90 (m,
8H), 7.37 (t, J = 7.9 Hz, 8H), 7.19–7.09 (m, 4H), 6.85 (s, 4H), 3.14–
2.81 (br s, 4H), 2.32 (br s, 4H), 1.81–1.62 (m, 4H). 13C{1H} NMR
(125 MHz, chloroform-d) δ 168.6, 139.1, 137.2, 137.0, 129.6,
129.2 124.5, 120.1, 33.4, 29.9, 27.9. HRMS (ESI) m/z: [M+H]+
calc’d for C46H41N4O4: 713.3122, found: 713.3121.
(±)-5,8,14,17-Tetra(n-hexyl)amide[3.3]paracyclophane ((±)-1a).
Oxalyl chloride (0.090 mL, 1.0 mmol) was added to a solution of
(±)-8 (73 mg, 0.18 mmol) in DCM (5 mL). A catalytic amount of
DMF (1 drop) was added and the mixture was stirred at rt for 2 h.
Then solvent and unreacted oxalyl chloride were removed in vacuo.
The resulting acid chloride intermediate was dissolved in DCM (5
mL). After cooling the solution to 0 °C, n-hexylamine (0.12 mL,
0.88 mmol) and N,N-diisopropylethylamine (DIPEA) (0.15 mL,
0.88 mmol) were added dropwise at 0 °C and the reaction mixture
was allowed to warm to rt over 2 h. The reaction mixture was
stirred overnight and then diluted with DCM and washed with 2 N
HCl (2 × 10 mL), H2O, and brine. The organic layer was separated,
dried with MgSO4, filtered, and the solvent was removed under
reduced pressure. The product was further purified by silica gel
chromatography (10–50% ethyl acetate in hexanes) and was
obtained as a near white solid (30 mg, 22% yield). Further
recrystallization by slow cooling a DMF/H2O solution yielded
shiny white crystals. 1H NMR (500 MHz, chloroform-d): 7.68
(br s, 4H), 7.01 (s, 4H), 3.45 (m, 8H), 3.11 (br s, 4H), 2.55 (br s,
4H), 1.94 (p, J = 5.5 Hz, 4H), 1.68 (m, 4H), 1.44 (m, 4H), 1.38 (m,
8H), 0.92 (t, J = 7.0 Hz, 4H). 13C{1H} NMR (125 MHz, CDCl3):
170.3, 137.4, 137.0, 129.5, 40.1, 31.7, 29.9, 29.5, 27.9, 27.0, 22.8,
14.2. HRMS (DART) m/z: [M+H]+ calc’d for C46H73N4O4:
745.5626, found 745.5633.
(±)-5,8,14,17-Tetraethylamide[3.3]paracyclophane
((±)-1e).
Synthesized in the same way as (±)-1a using (±)-8 (12 mg, 0.029
mmol), oxalyl chloride (0.02 mL, 0.3 mmol), ethylamine 2.0 M in
THF (1.0 mL, 2.0 mmol), and N,N-diisopropylethylamine (DIPEA)
(0.10 mL, 0.57 mmol). The product was further purified by silica
gel chromatography (0–10% methanol in DCM) and was obtained
as an off-white solid (5 mg, 33% yield). Further purification by
recrystallization from methanol yielded pure (±)-1e as small
colorless needles. 1H NMR (500 MHz, chloroform-d) δ 7.50 (br s,
4H), 7.06 (s, 4H), 3.52 (m, 8H), 3.16 (br s, 4H), 2.58 (br s, 4H),
1.97 (br s, 4H), 1.32 (t, J = 7.3 Hz, 12H). 13C{1H} NMR (125 MHz,
chloroform-d) δ 170.4, 137.4, 137.0, 129.5, 41.9, 29.9, 27.9, 22.9,
11.9. HRMS (ESI) m/z: [M+H]+ calc’d for C30H41N4O4: 521.3122,
found: 521.3107.
(±)-5-Carboxy[3.3]paracyclophane ((±)-9). This compound was
synthesized in the same way as (±)-8, with (±)-6 (17 mg, 0.54
mmol), t-BuLi (1.5 M in hexanes, 2 mL, 3 mmol), and CO2 (16 g,
0.36 mol) to yield a white powder (128 mg, 84% yield). Silica gel
chromatography (70% ethyl acetate in hexanes) had significant
coelution with pivalic acid by-product so the product was used
without further purification. 1H NMR (400 MHz, chloroform-d) δ
7.56–7.44 (s, 1H), 6.87–6.62 (m, 6H), 3.80 (m, 1H), 3.08–2.45 (m,
7H), 2.31–1.99 (m, 4H). 13C{1H} NMR (100 MHz, chloroform-d)
δ 173.9, 142. 1, 139.2, 138.7, 138.5, 138.3, 134.9, 133.6, 132.3,
130.6, 129.7, 129.2, 127.4, 38.8, 36.1, 36.0, 35.6, 35.5, 34.9, 29.9,
29.6, 29.0. HRMS (ESI) m/z: [M–H]– calc’d for C19H19O2:
(±)-5,8,14,17-Tetra(n-propyl)amide[3.3]paracyclophane ((±)-1b).
Synthesized in the same way as (±)-1a using (±)-8 (21 mg, 0.044
mmol), oxalyl chloride (0.048 mL, 0.58 mmol), n-propylamine
(0.10 mL, 1.2 mmol), and N,N-diisopropylethylamine (DIPEA)
ACS Paragon Plus Environment