The Journal of Organic Chemistry
Article
9-Dimethylaminomethyl-10-(triisopropylsilylethynyl)-
anthracene (5). A mixture of 3 (1.01 g, 3.70 mmol),
PdCl2(CH3CN)2 (9.6 mg, 37 μmol), 2-dicyclohexylphosphino-
2′,4′,6′-triisopropylbiphenyl (X-Phos) (53 mg, 0.111 mmol), CsCO3
(3.13 g, 9.62 mmol), and TIPS-acetylene (1.01 g, 5.55 mmol) in
MeCN (50 mL) was stirred at 90 °C for 24 h. The mixture was
partitioned between EtOAc and H2O. The organic layer was washed
with brine, dried (Na2SO4), and concentrated. The residue was
purified by column chromatography (SiO2, 10−20% MeOH in
1H NMR (600 MHz, CDCl3) δ 8.97 (2H, d, J = 8.9), 8.95 (1H, s),
8.62 (1H, m), 8.54 (2H, d, J = 8.2), 8.35 (1H, s), 7.69−7.67 (2H, m),
7.62−7.59 (2H, m), 7.42−7.41 (2H, m), 7.32−7.27 (7H, m), 6.54
(1H, t, J = 6.9), 4.74−4.73 (1H, m), 4.42 (2H, s), 4.20−4.18 (1H, m),
3.77 (6H, s), 3.48−3.42 (2H, m), 2.95−2.91 (1H, m), 2.63−2.61 (6H,
s), 2.39 (6H, s); 13C NMR (150 MHz, CDCl3) δ 158.6, 152.6, 151.0,
149.7, 144.5, 143.9, 142.2, 136.0, 135.6, 135.3, 134.5, 133.2, 130.7,
130.0, 128.1, 127.9, 127.6, 127.1, 127.0, 126.3, 125.3, 123.8, 115.9,
113.2, 96.4, 95.8, 86.6, 86.2, 84.6, 72.4, 63.6, 55.4, 55.2, 45.7, 40.1;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C50H46N5O5 796.3499;
found 796.3519.
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CHCl3) to give 5 (1.28 g, 83%): H NMR (500 MHz, CDCl3) δ
8.70−8.69 (2H, m), 8.50−8.48 (2H, m), 7.59−7.54 (4H, m), 4.37
(2H, s), 2.36 (6H, s), 1.30−1.26 (21H, m); 13C NMR (125 MHz,
CDCl3) δ 132.7, 131.9, 130.8, 127.5, 126.1, 125.9, 125.2, 118.4, 103.6,
103.2, 55.3, 45.6, 18.9, 11.5; HRMS (ESI-TOF) m/z [M + H]+ calcd
for C28H38NSi 416.2774; found 416.2770.
9-Dimethylaminomethyl-10-ethynylanthracene (6). To a
solution of 5 (0.354 g, 0.852 mmol) in THF (8 mL) was added
TBAF (1 M in THF, 1.7 mL), and the mixture was stirred at room
temperature for 3 h. The solvent was evaporated in vacuo, and the
resulting residue was purified by column chromatography (SiO2, 20−
50% EtOAc in hexane) to give 6 (0.182 g, 82%): 1H NMR (500 MHz,
CDCl3) δ 8.66−8.64 (2H, m), 8.52−8.50 (2H, m), 7.60−7.56 (4H,
m), 4.38 (2H, s), 4.01 (1H, s), 2.38 (6H, s); 13C NMR (125 MHz,
CDCl3) δ 132.8, 132.5, 130.7, 127.3, 126.3, 126.0, 125.2, 116.8, 88.5,
80.6, 55.3, 45.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H18N
260.1439; found 260.1439.
3′-O-[(2-Cyanoethoxy)(N,N-diisopropylamino)]phosphanyl-
6-deamino-2′-deoxy-5′-O-(4,4′-dimethoxytrityl)-6-[(10-dime-
thylaminomethylanthracen-9-yl)ethynyl]adenosine (13). A
mixture of 12 (0.130 g, 0.163 mmol), N,N-diisopropylethylamine
(0.171 mL, 0.978 mmol), and chloro(2-cyanoethoxy)(N,N-
diisopropylamino)phosphine (73 μL, 0.326 mmol) in THF (1 mL)
was stirred at room temperature for 1 h. The mixture was partitioned
between CHCl3 and aqueous NaHCO3 (saturated). The organic layer
was washed with brine, dried (Na2SO4), and concentrated. The
residue was purified by column chromatography (SiO2, 50% EtOAc in
1
hexane) to give 13 (0.184 g, 100%): H NMR (600 MHz, CDCl3) δ
8.98 (1H, s), 8.96 (2H, d, J = 2.8), 8.54 (d, 2H, J = 8.9), 8.39 (d, 1H, J
= 17.2), 7.69−7.67 (2H, m), 7.62−7.59 (2H, m), 7.43−7.41 (2H, m),
7.32−7.30 (4H, m), 7.29−7.27 (2H, m), 7.23−7.20 (1H, m), 6.82−
6.79 (4H, m), 6.58−6.55 (1H, m), 4.84−4.79 (1H, m), 4.42 (2H, s),
4.37−4.35 (1H, m), 3.91−3.86 (1H, m), 3.81−3.78 (1H, m), 3.77
(6H, d, J = 3.4), 3.73−3.69 (1H, m), 3.66−3.60 (2H, m), 3.48−3.43
(1H, m), 3.42−3.36 (1H, m), 3.01−2.96 (1H, m), 2.77−2.74 (1H, m),
2.70−2.66 (1H, m), 2.64 (1H, t, J = 6.9), 2.49 (1H, t, J = 6.2), 2.40
(6H, s), 1.30−1.25 (3H, m), 1.22−1.19 (10H, m), 1.14 (3H, d, J =
6.8); 31P NMR (242 MHz, CDCl3) δ 149.7, 149.5; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C59H63N7O6P 996.4577; found 996.4559.
9-(Triisopropylsilylethynyl)anthracene (8). A mixture of 9-
chloroanthracene (7) (0.5 g, 2.35 mmol), PdCl2(CH3CN)2 (6 mg, 20
μmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-
Phos) (34 mg, 70 μmol), CsCO3 (2.0 g, 6.1 mmol), and TIPS-
acetylene (0.65 g, 3.5 mmol) in MeCN (5 mL) was stirred at 90 °C for
24 h. The mixture was partitioned between EtOAc and H2O. The
organic layer was washed with brine, dried (Na2SO4), and
concentrated. The residue was purified by column chromatography
(SiO2, hexane) to give 8 (0.70 g, 100%): 1H NMR (500 MHz, CDCl3)
δ 8.62 (2H, d, J = 8.6), 8.42 (1H, s), 8.00 (2H, d, J = 8.6), 7.58 (2H, t,
J = 8.0), 7.50 (2H, t, J = 7.5), 1.29−1.26 (17H, m), 1.20 (4H, d, J =
7.5); 13C NMR (125 MHz, CDCl3) δ 133.0, 131.1, 128.6, 127.7, 126.8,
126.7, 125.6, 117.6, 19.0, 18.9, 12.1, 11.5; HRMS (ESI-TOF) m/z [M
+ H]+ calcd for C25H31Si 359.2195; found 359.2174.
3′,5′-Bis-O-(tert-butyldimethylsilyl)-6-deamino-2′-deoxy-6-
[(10-dimethylaminomethylanthracen-9-yl)ethynyl]adenosine
(11). To a mixture of 3′,5′-bis-O-(tert-butyldimethylsilyl)-6-deamino-
2′-deoxy-6-iodoadenosine (10) (0.209 g, 0.354 mmol), PdCl2[P-
(C6H5)3]2 (20 mg, 28 μmol), CuI (10 mg, 53 μmol), and Et3N (1.9
mL, 14 μmol) was added a solution of 6 (0.135 g, 0.521 mmol) in
THF (5 mL). The reaction mixture was stirred at room temperature
for 24 h. The resulting mixture was filtered through a Celite pad, and
the eluant was concentrated. The residual oil was dissolved in CHCl3.
The organic layer was washed with brine, dried (Na2SO4), and
concentrated. The residue was purified by column chromatography
1
(SiO2, 40% EtOAc in hexane) to give 11 (0.230 g, 90%): H NMR
(500 MHz, CDCl3) δ 9.03 (1H, s), 9.00 (2H, d, J = 8.6), 8.57 (1H, s),
8.54 (2H, d, J = 8.6), 7.68 (2H, t, J = 6.3), 7.62−7.59 (2H, m), 6.58
(1H, t, J = 6.3), 4.69−4.68 (1H, m), 4.41 (2H, s), 4.07−4.06 (1H, m),
3.92 (1H, dd, J = 4.6, 11.5), 3.82 (1H, dd, J = 3.5, 11.5), 2.76−2.71
(1H, m), 2.55−2.50 (1H, m), 2.39 (6H, s), 0.94 (18H, d, J = 4.6), 0.13
(12H, d, J = 4.1); 13C NMR (125 MHz, CDCl3) δ 152.6, 151.0, 143.9,
142.2, 135.4, 134.4, 133.3, 130.7, 127.7, 127.0, 126.3, 125.2, 116.0,
96.3, 95.8, 88.0, 84.5, 71.7, 62.7, 55.4, 45.7, 41.3, 26.0, 18.4, 18.0, −4.7,
−4.8, −5.4, −5.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C41H56N5O3Si2 722.3922; found 722.3923.
6-Deamino-2′-deoxy-6-[(10-dimethylaminomethylanthra-
cen-9-yl)ethynyl]adenosine (1). To a solution of 11 (0.230 g, 0.318
mmol) in THF (5 mL) was added TBAF (1 M in THF, 1.3 mL), and
the mixture was stirred at room temperature for 3 h. The solvent was
evaporated in vacuo, and the resulting residue was purified by column
chromatography (SiO2, 1−10% MeOH in CHCl3) to give 1 (0.191 g,
100%): 1H NMR (500 MHz, CDCl3) δ 9.01 (1H, s), 8.96 (2H, d, J =
8.7), 8.54 (2H, d, J = 8.7), 8.39 (1H, s), 7.70−7.58 (4H, m), 6.52−
6.49 (1H, m), 4.54 (1H, s), 4.41 (2H, s), 4.25 (1H, s), 4.01 (1H, d, J =
13.3), 3.89 (1H, d, J = 13.3), 3.09−3.02 (1H, m), 2.50−2.42 (1H, m),
2.39 (6H, s); 13C NMR (125 MHz, CDCl3) δ 152.9, 150.4, 144.9,
143.0, 136.3, 134.8, 133.3, 130.7, 127.5, 127.2, 126.3, 125.3, 115.6,
97.4, 95.6, 89.4, 87.5, 73.0, 63.2, 55.3, 45.7, 40.9; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C29H28N5O3 494.2192; found 494.2190.
6-Deamino-2′-deoxy-5′-O-(4,4′-dimethoxytrityl)-6-[(10-di-
methylaminomethylanthracen-9-yl)ethynyl]adenosine (12). A
mixture of 1 (0.136 g, 0.246 mmol) and DMTrCl (0.122 g, 0.359
mmol) in pyridine (5 mL) was stirred at room temoerature. After 3 h,
the mixture was partitioned between EtOAc and aqueous NaHCO3
(saturated). The organic layer was washed with brine, dried (Na2SO4),
and concentrated. The residue was purified by column chromatog-
raphy (SiO2, 33−100% EtOAc in hexane) to give 12 (0.130 g, 59%):
9-Ethynylanthracene (9). To a solution of 8 (0.70 g, 3.0 mmol)
in THF (5 mL) was added TBAF (1 M in THF, 6 mL), and the
mixture was stirred at room temperature for 3 h. The solvent was
evaporated in vacuo, and the resulting residue was purified by column
1
chromatography (SiO2, hexane) to give 9 (0.36 g, 59%): H NMR
(500 MHz, DMSO-d6) δ 8.71 (1H, s), 8.45 (2H, d, J = 8.6), 8.16 (2H,
d, J = 8.0), 7.69−7.66 (2H, m), 7.59 (2H, t, J = 7.0), 5.17 (1H, s); 13C
NMR (125 MHz, CDCl3) δ 133.2, 131.0, 128.7, 128.2, 126.8, 126.5,
125.7, 116.0, 88.2, 80.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C16H11 203.0861; found 203.0879.
6-(Anthracen-9-yl)ethynyl-3′,5′-bis-O-(tert-butyldimethylsil-
yl)-6-deamino-2′-deoxyadenosine (14). To a mixture of 10 (0.57
g, 2.84 mmol), PdCl2[P(C6H5)3]2 (90 mg, 0.13 mmol), CuI (50 mg,
0.24 mmol), and Et3N (65 μL, 0.6 mmol) was added a solution of 9
(0.96 g, 1.62 mmol) in THF (10 mL). The reaction mixture was
stirred at room temperature for 24 h. The resulting mixture was
filtered through a Celite pad, and the eluant was concentrated. The
residual oil was dissolved in CHCl3. The organic layer was washed
with brine, dried (Na2SO4), and concentrated. The residue was
purified by column chromatography (SiO2, 40% EtOAc in hexane) to
1
give 14 (0.86 g, 80%): H NMR (500 MHz, CDCl3) δ 9.04 (1H, s),
8.93 (2H, d, J = 8.0), 8.57 (1H, s), 8.55 (1H, s), 8.05 (2H, d, J = 8.6),
7.70−7.67 (2H, m), 7.56 (2H, t, J = 8.0), 6.58 (2H, t, J = 6.3), 4.69−
H
J. Org. Chem. XXXX, XXX, XXX−XXX