The Journal of Organic Chemistry
Article
chromatography on silica gel (eluent: cyclohexane, Rf = 0.7). The
product is a white powder. Yield: 2.060 g (4.34 mmol, 80%); mp 161
°C; 1H NMR (400.1 MHz, CDCl3, 293 K) δ = 2.84−2.92 (m, 2 H, H-
1, H-2), 3.03−3.20 (m, 2 H, H-1, H-2), 3.21−3.22 (m, 4 H, H-9,H-
10), 6.50 (dd, 2 H, H-7, H-12, 3J7,8 = 3J12,13 = 7.8 Hz, 4J7,5 = 4J12,16 = 1.8
Hz),6.91 (d, 2 H, H-5, H-16, 4J5,7 = 4J16,12 = 1.8 Hz) 7.20 (d, 2 H, H-8,
H-1*, H-2*), 2.83−2.97 (m, 4 H, H-9*, H-10*), 3.35 (bs, 4H, N−H),
5.45 (d, 2 H, H-5, H-16, 4J5,7 = 4J16,12 = 1.8 Hz), 5.97 (dd, 2 H, H-7, H-
12, 3J7,8 = 3J12,13 = 7.7 Hz, 4J7,5 = 4J12,16 = 1.8 Hz), 6.92 (d, 2 H, H-8, H-
3
13, J8, 7
=
3J13,12 = 7.7 Hz) ppm; 13C {1H} NMR (100.6 MHz,
CD2Cl2, 293 K) δ = 29.7 (C-1*, C-2*), 35.0 (C-9*, C-10*), 120.7 (C-
5, C-16), 122.3 (C-7, C-12), 124.0 (C-3, C-14), 128.7 (C-8, C-13),
140.8 (C-6, C-11), 146.2 (C-4, C-15) ppm (* assignment might be
interchanged); MS (EI) m/z (%) = 238.1 (50) [C16H18N2]+•, 119.0
(100) [C8H9N]+, 91 (10) [C7H7]+; EI-HRMS m/z calcd. for
[C16H18N2]+· 238.1470, found 238.1472.
3
3
H-13, J8,7 = J13,12 = 7.8 Hz) ppm; 13C {1H} NMR (100.6 MHz,
CDCl3, 293 K δ = 34.8 (C-1, C-2), 36.9 (C-9, C-10), 104.9 (C-4, C-
15), 129.5 (C-8, C-13), 131.9 (C-7, C-12), 141.0 (C-6, C-11), 142.7
(C-3, C-14), 142.8 (C-5, C-16); MS (EI) m/z (%) 459.9 (100)
[C16H14I2]+, 229.9 (60) [C8H7I]+; ESI-HRMS m/z calcd. for
[C16H14I2]+ 459.9185, found 459.9192.
Separation of Enantiomers. HPLC [chiral phase (semiprepar-
ative): CHIRALPAK IB; n-hexane/EtOH (70:30); f = 20.0 mL/min;
loading 40 mg of racemic material per run] tR = 11.86 [(+)-(SP)-12
(RP)-4,15-Diiodo[2.2]paracyclophane {(RP)-(10)}. Enantiomeri-
cally pure (RP)-12 (0.100 g, 0.43 mmol) was dissolved in conc. HCl
(1.5 mL) and diluted with water (5 mL). The stirred solution was
cooled to 0 °C and NaNO2 (0.070 g, 1.03 mmol) dissolved in water
(2.5 mL) was slowly added. After 30 min. KI (0.374 g, 2.25 mmol)
dissolved in water (2 mL) was added at 0 °C. The solution was stirred
at 0 °C for 30 min and was then heated to 80 °C for 2 h. After cooling
to room temperature the solution was extracted with dichloromethane
(3 × 20 mL). The combined organic phases were washed with
saturated aqueous NaHSO3 solution and brine and dried over MgSO4.
The solvent was evaporated under reduced pressure and crude 10 was
purified by column chromatography on silica gel (eluent: cyclohexane,
Rf = 0.7). The product is a white powder. Yield: 0.152 g (0.32 mmol,
74%). Suitable crystals for X-ray diffraction analysis were grown from a
mixture of cyclohexane and ethyl acetate.
20
[α]D20 = +95 (c = 2.55 g/mL, THF), 99.9% ee], 15.55 [(−)-(RP)-12
[α]D = −97 (c = 3.15 g/mL, THF), 99.9% ee] min.
(rac)-4,15-Di-(4,4,5,5-tetramethyl-1,3,2-dioxborolan)-[2.2]-
paracylcophane {(rac)-13}. 7.20 mL of tBuLi (1.9 M in pentane,
13.70 mmol) were added to 40 mL of dry THF at −78 °C and stirred
for 5 min. To the flashy yellow solution (rac)-3 (1.000 g, 2.74 mmol)
dissolved in THF (20 mL) was added via a syringe. The mixture was
stirred for 1 h at −78 °C turning from flashy yellow to pale yellow.
Then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.530 g,
1.66 mL, 8.22 mmol) in 10 mL of dry THF was added, and the
solution was allowed to slowly warm to room temperature, thereby
first turning to pale green and then colorless. The reaction was
quenched by the addition of water and ethyl acetate. The phases were
separated, and the aqueous phase was extracted with ethyl acetate (2 ×
40 mL). The combined organic phases were washed with water and
brine and dried over MgSO4. The crude product was purified by
column chromatography on silica gel (cyclohexane/ethyl acetate, 10:1
v/v, Rf = 0.5), yield 1.196 g (2.60 mmol, 95%). The product is a white
20
Compound (−)-(RP)-10: [α]D = −245 (c = 3.20 mg/mL,
CHCl3).
(rac)-[2.2]Paracyclophane-4,15-diazide {[rac)-11}. 7.20 mL of
tBuLi (1.9 M in pentane, 13.70 mmol) were added to 40 mL of dry
THF at −78 °C and stirred for 5 min. To the flashy yellow solution
(rac)-3 (1.000 g, 2.74 mmol) dissolved in THF (20 mL) was added via
a syringe. The mixture was stirred for 1 h at −78 °C turning from
flashy yellow to pale yellow. Then p-toluenesulfonyl azide (1.608 g,
8.16 mmol) in 10 mL of dry THF was added slowly to the stirred
solution. The solution was allowed to slowly warm to room
temperature, turning from pale yellow to red and then to black. The
reaction mixture is poured into saturated ammonium chloride solution,
and the aqueous layer was extracted with dichloromethane (3 × 60
mL). The combined organic layers were washed with brine and dried
over MgSO4. The solvent was removed under reduced pressure and
crude 11 was purified via column chromatography on silica gel
(cyclohexane, Rf = 0.4) to remove remaining p-toluenesulfonate. The
mixture still contains monoazide byproduct. The product mixture is a
1
powder: mp 190 °C; H NMR (400.1 MHz, acetone-d6, 293 K) δ =
1.41 (s, 12 H, CH3), 2.86−2.94 (m, 2H, H-1, H-2), 2.95−3.05 (m, 2H,
H-9, H-10), 3.10−3.20 (m, 2H, H-9, H-10), 3.85−3.95 (m, 2H, H-1,
H-2), 6.37 (d, 2H, H-8, H-13, 3J8,7 = 3J13,12 = 7.7 Hz), 6.52 (dd, 2H, H-
3
3
4
7, H12, J7, 8 = J12,13 = 7.7 Hz, 4J7,5 = 4J12,16 = 2.0 Hz), 7.00 (d, J5,7
=
4J16, 12 = 2.0 Hz, 2H, H-5, H-16), ppm; 13C {1H} NMR (100.4 MHz,
acetone-d6, 293 K) δ = 24.8 (CH3), 25.1 (CH3), 35.39 (C-1, C-2),
36.42 (C-1, C-2), 83.6 (Cquaternary), 134.3 (C-8, C-13), 135.3 (C-7, C-
12), 138.8 (C-6, C-11), 140.9 (C-5, C-16), 148.0 (C-3, C-14) ppm.
The carbon connected to the boron cannot be seen in the NMR
spectrum because of its low intensity due to the coupling to the boron.
11B {1H} NMR (128.4 MHz, acetone-d6, 293 K) 31.23 (bs) ppm; MS
(ESI) m/z (%) = 461.3 (50) [C28H38B2O4+H]+•, 483.3 (100)
[C28H38B2O4+Na]+; ESI-HRMS m/z calcd. for [C28H38B2O4+Na]+
483.2858, found 483.2863. Elemental analysis calcd (%) for
C28H38B2O4 (460.22): C 73.07, H 8.32. Found: C 72.96, H 8.18.
Separation of Enantiomers. HPLC [chiral phase (preparative):
1
pale yellow solid: H NMR (400.1 MHz, CDCl3, 293 K) δ = 2.75−
2.84 (m, 2 H, H-1, H-2), 2.99−3.12 (m, 4 H, H-1, H-9), 3.14−3.23
4
4
(m, 2 H, H-1, H-2), 6.01 (d, 2 H, H-5, H-16 J5,7 = J16,12 = 1.7 Hz),
3
3
4
4
6.38 (dd, 2 H, H-7, H-12, J7,8 = J12,13 = 7.9 Hz, J7,5 = J12,16 = 1.7
Hz), 6.84 (d, 2 H, H-8, H-13, 3J8,7 = 3J13,12 = 7.9) ppm; 13C {1H} NMR
(100.6 MHz, CDCl3, 293 K) δ = 30.8 (C-1, C-2), 34.7 (C-9, C-10),
123.8 (C-5, C-16), 128.0 (C-7, C-12), 131.1 (C-8, C-13), 133.2 (C-3,
C-14), 140.8 (C-6, C-11), 146.2 (C-4, C-15) ppm; MS (EI) m/z (%)
= 290.1 (25) [C16H14N6]+•; EI-HRMS m/z calcd. for [C16H14N6]+·
290.1280, found 290.1282.
CHIRALPAK IB; n-hexane/CHCl3 (98:2); f = 9.0 mL/min; loading
20
10 mg of racemic material per run] tR = 15.03 [(+)-(SP)-13 [α]D
+158 (c = 2.010 g/mL, EtOH), >99.9% ee], 17.48 [(−)-(RP)-13 [α]D
= −158 (c = 2.29 g/mL, EtOH), 98.7% ee] min.
=
20
(SP)-4,15-Di{(4-bromophenyl)hydrazone}[2.2]paracyclo-
phane {(SP)-14}. 4-Bromohydrazine (0.45 g) was dissolved in conc.
H2SO4 (2 mL) and water (3 mL). EtOH (10 mL) was added to this
solution and precipitate was filtered off. (SP)-5 (0.100 g, 0.273 mmol)
was dissolved in CH2Cl2 (2 mL) and added to the 4-bromohydrazine
solution. After keeping at room temperature overnight greenish
crystals were formed, which were filtered off and carefully washed with
water. These crystals were suitable for X-ray diffraction analysis: mp
(rac)-4,15-Diamino[2.2]paracyclophane {(rac)-12}. A round-
bottom flask was charged with tetrabutylammonium iodide (1.272 g,
3.44 mmol) and NaBH4 (2.612 g, 68.80 mmol) under an argon
atmosphere. Subsequently, (rac)-11 (1.000 g, 3.44 mmol), dissolved in
26.5 mL of dry THF, and 21.8 mL of water were added, and the
solution was stirred for 48 h at room temperature. Afterward
additionally NaBH4 (1.306 g, 34.40 mmol) was added, and the
mixture was stirred for further 24 h. The reaction mixture was then
poured into water and was extracted with Et2O (4 × 50 mL). The
combined organic layers were washed with brine and dried over
MgSO4. The solvent was evaporated under reduced pressure, and
crude 12 was purified by column chromatography on silica gel
(cyclohexane/ethyl acetate 2:1, v/v + 5% triethylamine, Rf = 0.5), yield
0.729 g (3.06 mmol, 73%). The product is a brownish solid: mp 232
1
218 °C; H NMR (400.1 MHz, CDCl3, 293 K) δ = 2.87−2.97 (m, 2
H, H-1, H-2), 2.98−3.09 (m, 2 H, H-9, H-10), 3.10−3.21 (m, 2 H, H-
9, H-10), 3.69−3.80 (m, 2 H, H-1, H-2) 6.45 (d, 2 H,H-7, H-12, 3J7,8
=
3J12,13 = 7.7 Hz), 6.59 (d, 2 H, H-8, H-13, 3J8,7 = 3J13, 12 = 7.7 Hz), 6.86
(s, 2 H, H-5, H-16), 7.03 (d, 4 H, H-phenyl, 3J = 8.8 Hz), 7.41 (d, 4 H,
H-phenyl, 3J = 8.8 Hz), 7.68 (s, 2 H, CHN) ppm; MS (ESI) m/z (%)
601.06 (100) [C30H26Br2N4+H]+, 623.0 (35) [C30H26Br2N4+Na]+;
ESI-HRMS m/z calcd. for [C30H26Br2N4+H]+ 601.0597, found
601.0574. Elemental analysis calcd (%) for C30H26Br2N4 (602.36)•2
H2O: C 56.44, H 4.74. Found: C 56.89, H 4.75.
1
°C; H NMR (400.1 MHz, CD2Cl2, 293 K) δ = 2.76−2.80 (m, 4 H,
6685
dx.doi.org/10.1021/jo501212t | J. Org. Chem. 2014, 79, 6679−6687