Functionalized Flavin Receptors
J . Org. Chem., Vol. 64, No. 26, 1999 9687
with CH2Cl2. After the residue was dried over MgSO4, CH2-
Cl2 was evaporated, and the residue was recrystallized from
EtOH to give colorless needle crystals: yield 7.9 g (97%); mp
recrystallized from CHCl3-diethyl ether: yield 0.47 g (50%);
mp 150-153 °C; 1H NMR (500 MHz) δ (ppm) 0.91 (t, J ) 7.00
Hz, 3H), 1.16 (t, J ) 7.00 Hz, 6H), 1.28-1.36, 1.43-1.54 (m,
4H), 3.29 (t, J ) 7.20 Hz, 2H), 3.50 (q, J ) 6.70 Hz, 4H), 4.44
(s, 2H), 4.51 (s, 2H), 5.25 (br s, 2H), 6.52 (br s, 4H), 7.20-7.35
(m, 5H). Anal. Calcd for C30H20N9O4Cl: C, 48.04; H, 6.85; N,
25.21. Found: C, 47.82; H, 6.72; N, 24.90.
1
99-101 °C; H NMR (200 MHz) δ (ppm) 0.93 (t, J ) 7.0 Hz,
3H), 1.18 (t, J ) 7.0 Hz, 6H), 1.30-1.60 (m, 4H), 3.38 (q, J )
6.2 Hz, 2H), 3.57 (q, J ) 7.0 Hz, 4H), 5.15-5.27 (br s, 1H).
2-Bu tylam in o-4-dieth ylam in o-6-(2-eth oxycar bon ylam i-
n om eth ylben zyla m in o)-s-tr ia zin e (9a ). A mixture of 8 (3.10
g, 12 mmol), 2-ethoxycarbonylaminomethylbenzylamine (2.70
g, 12 mmol), and K2CO3 (1.82 g, 12 mmol) in dioxane (70 mL)
was refluxed overnight. After the solvent was evaporated in
vacuo, water was added and the mixture extracted with CH2-
Cl2. After the residue was dried over MgSO4, CH2Cl2 was
evaporated to dryness. The residue was purified by dry column
chromatography (SiO2, CH2Cl2/CH3COCH3) 7:1): oil; yield 3.5
g (69%); 1H NMR (200 MHz) δ (ppm) 0.92 (t, J ) 7.04 Hz, 3H),
1.12 (t, J ) 7.24 Hz, 6H), 1.23 (t, J ) 7.20 Hz, 3H), 1.30-1.60
(m, 4H), 3.32 (q, J ) 6.20 Hz, 2H), 3.50 (q, J ) 6.96, 4H), 4.15
(q, J ) 7.20 Hz, 2H), 4.44 (d, J ) 5.78 Hz, 2H), 4.63 (d, J )
5.86 Hz, 2H), 5.14 (br s, 3H), 7.22-7.37 (m, 4H).
1
1b: yield 75%; mp 128-130 °C (H2O); H NMR (500 MHz)
δ (ppm) 0.88 (t, J ) 7.35 Hz, 3H), 1.10 (t, J ) 6.70 Hz, 6H),
1.26-1.32, 1.43-1.69 (m, 4H), 3.26 (t, J ) 7.30 Hz, 2H), 3.50
(q, J ) 6.70 Hz, 4H), 4.22 (s, 2H), 4.47 (s, 2H), 4.97, 5.61 (br
s, 2H), 6.32 (br s, 4H), 7.06-7.26 (m, 5H). Anal. Calcd for
C
30H20N9O4Cl: C, 48.07; H, 6.86; N, 25.24. Found: C, 48.29;
H, 6.74; N, 25.05.
1
1c: yield 53%; mp 117-120 °C (CHCl3-diethyl ether); H
NMR (500 MHz) δ (ppm) 0.87 (t, J ) 7.35 Hz, 3H), 1.12 (t, J
) 6.70 Hz, 6H),1.26-1.34, 1.43-1.73 (m, 4H), 3.27 (t, J ) 7.30
Hz, 2H), 3,49 (q, J ) 6.70 Hz, 4H), 4.19 (s, 2H), 4.41 (s, 2H),
5.46, 5.93 (br s, 2H), 6.17 (br s, 4H), 7.13-7.18 (m, 5H). Anal.
Calcd for C30H20N9O4Cl‚3H2O: C, 43.36; H, 7.28; N, 22.75.
Found: C, 43.38; H, 7.24; N, 22.94.
2-Bu tylam in o-4-dieth ylam in o-6-(3-eth oxycar bon ylam i-
n om eth ylben zyla m in o)-s-tr ia zin e (9b): colorless powders
(88%); 1H NMR (500 Hz) δ (ppm) 0.92 (t, J ) 7.3 Hz, 3H), 1.05-
1.09 (m, 6H), 1.25 (t, J ) 7.05 Hz, 3H), 1.33-1.40, 1.49-1.55
(m, 4H), 3.34 (q, J ) 6.40 Hz, 2H), 3.43-3.57 (m, 4H), 4.14 (q,
J ) 7.35 Hz, 2H), 4.33 (d, J ) 5.8 Hz, 2H), 4.54 (d, J ) 4.3 Hz,
2H), 4.74, 5.04, 5.13 (br s, 3H), 7.14-7.29 (m, 4H). Anal. Calcd
for C22H35N7O2: C, 61.51; H, 8.21; N, 22.82. Found: C, 61.34;
H, 8.22; N, 22.63. 3-Ethoxycarbonylaminomethylbenzylamine
was prepared by reaction with m-xylylenediamine and ethyl
chloroformate in diethyl ether. Purification was performed by
column chromatography (CH2Cl2-MeOH ) 15:1): 1H NMR
(200 MHz) δ 1.26 (t, J ) 7.20 Hz, 3H), 3.87 (s, 2H), 4.14 (q, J
) 7.20 MHz, 2H), 4.39 (d, J ) 6.0 Hz,2H), 4.85-5.05 (br s,
1H), 7.16-7.36 (m, 4H).
2-Bu tylam in o-4-dieth ylam in o-6-(4-eth oxycar bon ylam i-
n om eth ylben zyla m in o)-s-tr ia zin e (9c): oil (58%); 1H NMR
(200 MHz) δ (ppm) 0.88 (t, J ) 7.16 Hz, 3H), 1.11 (t, J ) 6.96
Hz, 6H), 1.25 (t, J ) 7.12 Hz, 3H), 1.30-1.60 (m, 4H), 3.36 (q,
J ) 6.20 Hz, 2H), 3.50 (q, J ) 6.96 Hz, 4H), 4.13 (q, J ) 7.12
Hz, 2H), 4.36 (d, J ) 5.94 Hz, 2H), 4.57 (d, J ) 5.86 Hz, 2H),
4.72, 5.05 (br s, 3H), 7.25-7.28 (m, 4H).
2-Bu t yla m in o-4-d iet h yla m in o-6-(2-a m in om et h ylb en -
zyla m in o)-s-tr ia zin e (12a ) was obtained by alkaline hydroly-
sis of 9a . A solution of EtOH (150 mL)-3 M KOH (100 mL)
containing 12a (4.5 g, 10.5 mmol) was refluxed for 48 h. After
the solvent was evaporated in vacuo, water was added and
the mixture extracted with CH2Cl2. After the residue was dried
over MgSO4, CH2Cl2 was evaporated to dryness to afford an
oily product (TLC one spot): oil; yield 3.98 g (100%); 1H NMR
(200 MHz) δ (ppm) 0.92 (t, J ) 7.28 Hz, 3H), 1.14 (t, J ) 7.08
Hz, 6H), 1.30-1.60 (m, 4H), 3.36 (q, J ) 6,40 Hz, 2H), 3.52 (q,
J ) 7.08 Hz, 4H), 3.95 (s, 2H), 4, 65 (d, J ) 5.74 Hz, 2H), 4.67,
5.52 (br s, 2H), 7.22-7.40 (m, 4H).
2-Bu t yla m in o-4-d iet h yla m in o-6-(3-a m in om et h ylb en -
zylam in o)-s-tr iazin e (12b) was obtained similarly: oil (100%);
1H NMR (200 MHz3) δ (ppm) 0.92 (t, J ) 7.12 Hz, 3H), 1.12 (t,
J ) 7.0 Hz, 6H), 1.30-1.60 (m, 4H), 3.33 (q, J ) 6.5 Hz, 2H),
3.51 (q, J ) 7.0 Hz, 4H), 3.85 (s, 2H), 4.59 (d, J ) 4.3 Hz, 2H),
4.67, 4.97 (br s, 2H), 7.16-7.32 (m, 4H).
Compounds 2 were synthesized from 8 and R,ω-alkanedi-
amines (propane, butane, hexane), followed by the reaction of
S-ethylisothiuoronium bromide as described for 1. Since
purification of 14 was difficult, 14 was reacted with ethyl
chloroformate and purified by flash column chromatography
(CH2Cl2/EtOAc ) 1:1). Hydrolysis and introduction of a guani-
dinium ion were performed in an essentially same manner as
described for 1. Purification of 2 was performed by repeated
precipitation from CHCl3 and diethyl ether.
2-Bu tyla m in o-4-(3-N-eth oxyca r bon ya m in op r op yla m i-
n o)-6-d ieth yla m in o-s-tr ia zin e (11a ). A mixture of 8 (3.00
g, 11.7 mmol), 1,3-diaminopropane (1.0 mL, 11.5 mmol), and
K2CO3 (1.50 g, 11.7 mmol) in dioxane (30 mL)-H2O (20 mL)
was refluxed overnight. After evaporation of the solvent, H2O
was added and the mixture extracted with CH2Cl2. After the
residue was dried over MgSO4, the solvent was evaporated.
To the residue were added diethyl ether (50 mL), K2CO3 (1.23
g, 8.88 mmol), and ethyl chloroformate (0.9 mL, 9.4 mmol) and
the mixture stirred at 0 °C for 1 h and at room temperature
for 6 h. After evaporation of the solvent, H2O was added and
the mixture extracted with CH2Cl2. After the CH2Cl2 layer was
dried over MgSO4, the residue was purified by dry column
chromatography (SiO2, CH2Cl2-EtOAc ) 1:1) to give a color-
1
less oil: yield 1.52 g (46%); H NMR (200 MHz) δ (ppm) 0.93
(t, J ) 7.24 Hz, 3H), 1.15 (t,, J ) 7.16 Hz, 6H), 1.24 (t, J )
7.20 Hz, 3H), 1.30-1.59 (m, 4H), 1.60-1.73 (m, 2H), 3.21 (m.
2H), 3.30-3.48 (m, 4H), 3.52 (t, J ) 7.16 Hz, 4H), 4.13 (q, J )
7.20 Hz, 2H), 4.83 (br s, 3H).
2-Bu tylam in o-4-(4-N-eth oxycar bon ylam in obu tylam in o)-
1
6-d ieth yla m in o-s-tr ia zin e (11b): yield 42%; H NMR (200
MHz) δ (ppm) 0.92 (t, J ) 7.24 Hz, 3H), 1.14 (t, J ) 7.04 Hz,
6H,), 1.24 (t, J ) 7.22 Hz, 3H),1.30-1.60 (m, 8H), 3.20 (m,
2H), 3.29-3.43 (m, 4H), 3.51 (t, J ) 7.04 Hz, 4H), 4.14 (q, J )
7.22 Hz, 2H), 4.70 (br s, 3H).
2-Bu tyla m in o-4-(6-N-eth oxyca r bon yla m in oh exyla m i-
n o)-6-d ieth yla m in o-s-tr ia zin e (11c): yield 14%; 1H NMR
(200 MHz) δ (ppm) 0.93 (t,, J ) 7.5 Hz, 1.16 (t, J ) 7.25 Hz,
6H), 1.25 (m, 3H), 1.39 (m, 6H), 1.46-1.57 (m, 6H), 3.17-3.38
(m, 6H), 3.48-3.58 (m, 4H), 4.11 (m, 2H), 4.77 (br s, 3H).
Compounds 14 were obtained by hydrolysis of 11 and used
as crude products. Namely, a solution of EtOH (50 mL)-3 M
KOH (30 mL) containing 11a (1.52 g, 4.08 mmol) was refluxed
for 4 days. After evaporation of the solvent, H2O was added to
the residue and the mixture extracted with CH2Cl2. After the
residue was dried over MgSO4, the solvent was distilled in
vacuo. To this crude product (11a ) was added S-ethylthio-
uronium bromide (0.77 g, 4.15 mmol) in EtOH (15 mL), and
the solution was refluxed for 2 days. The solvent was distilled
in vacuo to give a white solid. This was purified by repeated
reprecipitation from CHCl3 and diethyl ether.
2-Bu t yla m in o-4-d iet h yla m in o-6-(4-a m in om et h ylb en -
zyla m in o)-s-tr ia zin e (12c): oil (94%); 1H NMR (200 MHz) δ
(ppm) 0.92 (t, J ) 7.26 Hz, 3H), 1.12 (t, J ) 6.96 Hz, 6H),
1.30-1.60 (m, 4H), 3.33 (q, J ) 6.50 Hz, 2H), 3.51 (q, J ) 6.96
Hz, 4H), 3.85 (s, 2H), 4.57 (d, J ) 5.86 Hz, 2H), 4.77, 5.08 (br
s, 2H), 7.27-7.29 (m, 4H). Compounds 12 were used without
purification.
Compounds 1 were prepared by the reaction of 12 with
S-ethylthiouronium bromide15c in ethanol.
1a . A solution of 12a (0.80 g, 1.9 mmol) and S-ethylthio-
uronium bromide (0.35 g, 1.9 mmol) in EtOH (20 mL) was
stirred under reflux for 3 d. After EtOH was evaporated, the
residue was washed with diethyl ether, dissolved in water (10
mL), and filtered. To the solution was added excess sodium
perchlorate. The precipitate was collected by filtration and
2a : yield 0.23 g (13%); mp 141-142 °C; 1Η NMR (500 MHz)
δ (ppm) 0.89 (t, J ) 7.5 Hz, 3H), 1.16 (t, J ) 8.75 Hz, 6H),
1.35 (m, 2H), 1.50 (m, 2H), 1.84 (br s, 2H), 3.38 (br s, 6H),
3.47 (m, 4H), 5.49-5.82 (br s, 2H), 6.92-7.07 (br s, 4H), 7.62