S. M. Devine et al. / Bioorg. Med. Chem. 18 (2010) 3078–3087
3085
4.1.12. N6-(3,5-Di-tert-butyl-4-hydroxyphenethyl)adenosine-50-
N-methylcarboxamide (5g)
149.4, 153.1, 153.6, 158.1, 170.8, 172.2. HR-MS (LSIMS) calcd for
34H44N7O6 (M+H) 646.3348, found 646.3351.
C
To a solution of compound 2 (100 mg, 0.32 mmol) in t-BuOH
(5 mL) was added DIPEA (167
lL, 0.96 mmol) and amine 3g
4.1.16. N6-[4-[2-[3,5-di-tert-butylbenzamido]ethyl]
phenyl]adenosine-50-N-methylcarboxamide (7b)
To a solution of 2 (100 mg, 0.32 mmol) in t-BuOH (5 mL) was
added DIPEA (167 lL, 0.96 mmol) and amine 6b (225 mg,
(95 mg, 0.38 mmol) and the mixture was heated at reflux for
24 h. The solution was then evaporated at reduced pressure onto
SiO2 and purified by column chromatography to give desired ribo-
side 5g (CHCl3/MeOH/NH3, 89:10:1, Rf = 0.25) (130 mg, 77%). 1H
NMR (CD3OD): d 1.37 (s, 18H), 2.86–2.91 (m, 5H), 3.82 (br s, 2H),
4.36 (d, J = 4.8 Hz, 1H), 4.51 (s, 1H), 4.76 (d, J = 7.8, 4.8 Hz, 1H),
6.02 (d, J = 7.8 Hz, 1H), 7.03 (s, 2H), 8.20 (s, 1H), 8.27 (s, 1H). 13C
NMR (CD3OD): d 24.7, 29.5, 34.1, 35.3, 42.0, 72.1, 73.6, 85.1, 89.2,
120.2, 124.9, 129.7, 137.8, 140.5, 147.7, 152.3, 152.4, 155.0,
0.65 mmol) and the mixture was heated at reflux for 48 h. The
solution was then evaporated at reduced pressure onto SiO2 and
purified by column chromatography to give the desired riboside
7b (CHCl3/MeOH/NH3, 89:10:1, Rf = 0.23) (123 mg, 61%). 1H NMR
(CD3OD): d 1.36 (s, 18H), 2.88 (s, 3H), 2.94 (t, J = 7.2 Hz, 2H), 3.63
(t, J = 7.2 Hz, 2H), 3.81 (s, 3H), 3.87 (s, 6H), 4.36 (d, J = 4.8 Hz,
1H), 4.51 (s, 1H), 4.77 (dd, J = 7.5, 4.8 Hz, 1H), 6.06 (d, J = 7.5 Hz,
1H), 7.28 (d, J = 8.4 Hz, 2H), 7.62 (m, 3H), 7.75 (d, J = 8.4 Hz, 2H),
8.31 (s, 1H), 8.39 (s, 1H). 13C NMR (CD3OD): d 24.7, 30.4, 34.5,
34.7, 41.3, 72.1, 73.5, 85.1, 89.2, 120.2, 120.9, 121.2, 125.3, 129.0,
134.0, 134.9, 137.1, 141.4, 148.6, 151.0, 152.1, 152.5, 169.9,
+
171.4. HR-MS (ESI) calcd for C27H39N6O5 (M+H) 527.2976, found
527.2985.
4.1.13. N-[2-(4-Aminophenyl)ethyl]-3,5-di-tert-butyl-4-
hydroxybenzamide (6b)
þ
To
0.92 mmol), EDCI (212 mg, 1.10 mmol) and HOBt (149 mg,
1.10 mmol) in DMF (5 mL) was added DIPEA (481 L, 2.76 mmol)
and p-aminoethylaniline (145 L, 1.10 mmol) and the mixture
a
solution of 3,5-di-tert-butylbenzoic acid (216 mg,
171.3. HR-MS (ESI) calcd for C34H44N7O5 (M+H) 630.3398, found
630.3413.
l
l
4.1.17. N6-[4-[2-[3,4,5-Trimethoxybenzamido]
was stirred at 25 °C for 16 h. The solution was then poured into
water, forming a light brown precipitate, which was filtered and
washed with water to give the amide 6b (301 mg, 93%) as a brown-
ish solid. 1H NMR (CDCl3): d 1.39 (s, 18H, 6 ꢁ CH3), 2.89 (t,
J = 6.5 Hz, 2H), 3.66 (br s, 2H), 3.71 (q, J = 6.5 Hz, 2H), 6.15 (br s,
1H), 6.72 (d, J = 8.2 Hz, 2H), 7.11 (d, J = 8.2 Hz, 2H), 7.55 (s, 2H),
7.59 (s, 1H). 13C NMR (CDCl3): d 31.4, 34.8, 34.9, 41.3, 115.4,
121.0, 125.4, 128.9, 129.7, 134.5, 145.0, 151.1, 168.1. ESMS calcd
for C23H33N2O+ (M+H) 353.5, found 353.2.
ethyl]phenyl]adenosine-50-N-methylcarboxamide (7c)
To a solution of 2 (100 mg, 0.32 mmol) in t-BuOH (5 mL) was
added DIPEA (167 lL, 0.96 mmol) and amine 6c (216 mg,
0.65 mmol) and the mixture was heated at reflux for 48 h. The
solution was then evaporated at reduced pressure onto SiO2 and
purified by column chromatography to give the desired riboside
7c (CHCl3/MeOH/NH3, 89:10:1, Rf = 0.14) (128 mg, 66%). 1H NMR
(CD3OD): d 2.88 (s, 3H), 2.92 (t, J = 7.2 Hz, 2H), 3.63 (t, J = 7.2 Hz,
2H), 3.81 (s, 3H), 3.87 (s, 6H), 4.35 (d, J = 4.8 Hz, 1H), 4.50 (s, 1H),
4.76 (dd, J = 7.5, 4.8 Hz, 1H), 6.05 (d, J = 7.5 Hz, 1H), 7.13 (s, 2H),
7.26 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 8.30 (s, 1H), 8.38
(s, 1H). 13C NMR (CD3OD): d 24.7, 34.6, 41.3, 55.4, 59.8, 72.1,
73.5, 85.1, 89.2, 104.6, 120.7, 120.8, 128.9, 129.8, 134.8, 137.1,
140.7, 141.3, 148.5, 152.1, 152.5, 153.0, 171.3, 173.7. HR-MS (ESI)
4.1.14. N-(4-Aminophenethyl)-3,4,5-trimethoxybenzamide (6c)
To
a solution of 3,4,5-trimethoxybenzoic acid (743 mg,
3.50 mmol), EDCI (805 mg, 4.20 mmol) and HOBt (567 mg,
4.20 mmol) in DMF (10 mL) was added DIPEA (1.83 mL, 10.5
mmol) and p-aminoethylaniline (553 lL, 4.20 mmol) and the reac-
+
calcd for C29H34N7O8 (M+H) 608.2463, found 608.2469.
tion mixture was stirred at 25 °C for 16 h. The reaction was poured
into water, forming a light brown precipitate, which was filtered
and washed with water to give the amide 6c (901 mg, 78%) as an
off-white solid. 1H NMR (CDCl3): d 2.86 (t, J = 6.5 Hz, 2H), 3.67–
3.70 (m, 4H,), 3.92 (s, 9H), 6.18 (br s, 1H), 6.70 (d, J = 8.1 Hz, 2H),
6.96 (s, 2H), 7.08 (d, J = 8.1 Hz, 2H). 13C NMR (CDCl3): d 34.7,
41.4, 56.2, 60.8, 104.1, 115.3, 128.6, 129.6, 130.2, 140.7, 145.0,
4.1.18. N6-[4-[2-[1,1,3,3-Tetramethylisoindolin-2-yloxyl-5-
amido]ethyl]phenyl]adenosine-50-N-methylcarboxamide (7d)
Compound 2 (64 mg, 1.10 equiv) and 1,1,3,3-tetramethylisoin-
dol-2-yloxyl-5-carboxylic acid N-[2-(4-aminophenyl)ethyl]amide
(6d) (66 mg, 0.186 mmol) were taken up in anhydrous t-BuOH
(4 mL). DIPEA (75 lL, 2.31 equiv) was added to the solution and
the reaction was refluxed under a nitrogen atmosphere for 43 h.
The reaction solvent was evaporated under vacuum to give an
off-white foam which was purified using column chromatography
(CHCl3/MeOH/NH3, 89:10:1). The title compound (7d) was isolated
as an off-white powder (87 mg, 74% yield). Mp 170 °C. HR-MS (ESI)
+
153.1, 167.1. ESMS calcd for C18H23N2O4 (M+H) 331.2, found
331.1.
4.1.15. N6-[4-[2-[3,5-Di-tert-butyl-4-hydroxybenzamido]
ethyl]phenyl]adenosine-50-N-methylcarboxamide (7a)
Compound 2 (60 mg, 1.16 equiv) and the substituted aniline 6a
(61 mg, 0.164 mmol) were dissolved in anhydrous t-BuOH (4 mL).
+
calcd for C32H38N8O6 (M+H) 630.2909, found 630.2911.
4.1.19. N-(4-(Aminomethyl)benzyl)-3,5-di-tert-butyl-4-
hydroxybenzamide (8a)
DIPEA (75 lL, 2.62 equiv) was added to the solution and the reac-
tion was refluxed under a nitrogen atmosphere for 43 h. At this
time, the reaction solvent was evaporated to give a yellow foam
which was then purified using column chromatography (CHCl3/
MeOH/NH3, 89:10:1). The title compound (7a) was isolated as an
off-white powder (81 mg, 78% yield). Mp 170 °C. 1H NMR (CD3OD)
: d 1.44 (s, 18H), 2.88 (s, 3H), 2.91 (t, J = 7.2 Hz, 2H), 3.60 (t,
J = 7.2 Hz, 2H), 4.34 (dd, J = 4.8, 1.2 Hz, 1H), 4.50 (d, J = 1.2 Hz,
1H), 4.76 (dd, J = 7.5, 4.8 Hz, 1H), 6.05 (d, J = 7.5 Hz, 1H), 7.28 (d,
J = 8.7 Hz, 2H), 7.61 (s, 2H), 8.33 (s, 1H), 8.41 (s, 1H). 13C NMR
(CD3OD) : d 26.2, 30.6, 35.3, 36.0, 41.3, 73.1, 74.4, 86.2, 90.5,
121.9, 122.3, 125.2, 126.2, 130.3, 136.3, 137.7, 137.8, 141.8,
To a stirred solution of p-xylylenediamine (544 mg, 3.99 mmol)
in DMF (10 mL) at 0 °C was added dropwise, a solution of 3,5-di-
tert-butyl-4-hydroxy-benzoic acid (200 mg, 0.80 mmol), EDCI
(169 mg, 0.88 mmol), HOBt (119 mg, 0.88 mmol) and DIPEA
(417 lL, 2.39 mmol) in DMF (5 mL). The resultant mixture was stir-
red for 16 h at 25 °C, at which time it was poured onto ice/water
(100 mL) and stirred for 1 h. The small amount of precipitate that
formed was filtered, washed with water and the filtrate extracted
with CHCl3 (3 ꢁ 30 mL), washed with brine, dried over MgSO4, fil-
tered and the filtrate evaporated to give the amide 8a (109 mg,
37%) as a yellow oil. 1H NMR (DMSO): d 1.38 (s, 18H), 4.43 (d,