Jadhav and Schmidtchen
isomer 10 (245 mg). Thus, the overall yield of bicyclic guanidinium
compound 2 in two steps was 45% along with 20% structural isomer
10.
initial suspension disappeared to give a clear solution, and then
product started precipitating out from the reaction mixture. After
being stirred for 30 min, the reaction mixture was evaporated to
dryness by a jet of nitrogen and the colorless residue was used in
further reaction without any purification.
2. C41H53N3O2Si2‚HI (MW 804.0). HPLC analysis: Rv ) 14 mL,
RP Aqua C18, 250 × 4.60 mm, 5 µm column, UV254, flow ) 1
mL/min, gradient from 80% CH3OH to 90% CH3OH in 5 min and
then 90% CH3OH for 10 min more, 0.1% TFA as a buffer. MS-
ESI m/z ) 676.6 [(M + H)+, 100]. HRMS (micrOTOF-Q) calcd
for C41H53N3O2Si2+ 676.3749, found 676.3733. 1H NMR (360 MHz;
CDCl3): δ ) 8.07 (s, 2H, guanidinium-H), 7.61-7.64 (m, 8H,
aromatic), 7.36-7.43 (m, 12H, aromatic), 3.77-3.81 (m, 2H,
-CHCH2-), 3.58-3.62 (m, 4H, -CH2OSi-), 3.11-3.24 (m, 4H,
-NCH2-), 1.89-1.99 (m, 4H, -CHCH2-), 1.06 (s 18H, t-butyl-
CH3). 13C NMR (62.9 MHz; CDCl3): δ ) 151.1 (guanidinium
carbon), 135.6, 132.4, 130.0, 130.1, 127.9 (aromatic carbons), 65.3
(-CH2OSi-), 49.4 (-CHCH2-), 45.0 (N-CH2), 26.9 (tert-butyl-
CH3), 22.7 (-CHCH2-), 19.2 (quaternary carbons).
14. C11H21N3O6S2‚HCl (MW 391.9). HPLC analysis: Rv ) 10
mL, RP Aqua C18, 250 × 4.60 mm, UV254, flow ) 1 mL/min,
gradient from 10% CH3OH to 50% CH3OH in 10 min and then to
90% CH3OH in next 10 min, 0.1% TFA as a buffer. 1H NMR (360
MHz; CD3CN): δ ) 9.03 (bs, 2H, guanidinium), 4.27 (dd, 2H,
-CH2O-), 4.12 (dd, 2H, -CH2O-), 3.74-3.80 (m, 2H, -CHCH2-
), 3.26-3.37 (m, 4H, -NCH2-), 3.21 (s, 6H, -SCH3), 2.01-2.08
(m, 2H, -CHCH2-), 1.78-1.86 (m, 2H, -CHCH2-); 13C NMR
(90.56 MHz; CD3CN): δ ) 152.7 (guanidinium carbon), 71.5
(-CH2O-), 48.3 (-CHCH2-), 45.5 (-NCH2-), 37.9 (-SCH3),
22.6 (-CHCH2-).
(2S,8S)-2,8-Diazidomethyl-3,4,6,7,8,9-hexahydro-2H-pyrimido-
[1,2-a]pyrimidine Hydroperchlorate 15. The reaction residue
obtained above containing the bicyclic guanidinium compound 14
(1.24 mmol) was dissolved in absolute DMF (20 mL), and finely
powdered sodium azide (1.5 g, 23 mmol) was added. The mixture
was stirred in an oil bath at 90 °C. After being stirred overnight,
the reaction mixture was cooled to room temperature and then DMF
was removed under reduced pressure. The solid residue obtained
was taken up in dichloromethane (20 mL), and the insoluble part
was filtered and washed with dichloromethane (2 × 10 mL). The
combined dichloromethane layers were washed with nearly satu-
rated aqueous NaClO4 solution (2 × 30 mL), dried over magnesium
sulfate, and evaporated in vacuo to leave a gummy substance which
was recrystallized from methanol/water to furnish bisazide 15 (260
mg, 60% over three steps) as a colorless crystalline compound.
15. C9H15N9‚HClO4 (MW 349.7). HPLC analysis: Rv ) 12 mL,
RP Aqua C18, 250 × 4.60 mm, 5 µm column, UV254, flow ) 1
mL/min, gradient from 10% CH3OH to 50% CH3OH in 10 min
and then to 90% CH3OH in next 10 min, 0.1% TFA as a buffer.
IR (methanol) ν: 2109 cm-1 (N3).
(2S,8S)-2,8-Diaminomethyl-3,4,6,7,8,9-hexahydro-2H-pyrimido-
[1,2-a]pyrimidine Hydroperchlorate 11. To a solution of bisazide
15 (260 mg, 0.74 mmol) dissolved in methanol (25 mL) was added
10% Pd-C (50 mg).The suspension was stirred at room temperature
under an atmosphere of H2. After being stirred for 3 h, the reaction
mixture was filtered through a pad of Celite, and the evaporation
of filtrate gave bisaminoguanidinium compound 11 (211 mg, 95%)
as a gummy substance which solidified on standing.
11. C9H19N5‚HClO4 (MW 297.7). HPLC analysis: Rv ) 4 mL,
RP Aqua C18, 250 × 4.60 mm, 5 µm column, UV254, flow ) 1
mL/min, gradient from 10% CH3OH to 50% CH3OH in 10 min
and then to 90% CH3OH in next 10 min, 0.1% TFA as a buffer.
MS-ESI m/z ) 198.3 [(M + H)+, 100]. HRMS (micrOTOF-Q)
calcd for C9H20N5+ 198.1713, found 198.171. 1H NMR (360 MHz;
CD3OD): δ ) 3.33-3.42 (m, 6H, -CHCH2-, -CH2NH2), 2.68-
2.83 (m, 4H, -NCH2-), 2.05-2.10 (m, 2H, -CHCH2-), 1.80-
1.89 (m, 2H, -CHCH2-). 13C NMR (90.56 MHz; CD3OD): δ )
152.3 (guanidinium carbon), 51.8 (-CHCH2-), 46.3 (-CH2NH2),
46.1 (-NCH2), 24.7 (-CHCH2-).
(2S,6R)-2,6-Di[[(tert-butyldiphenylsilyl)oxy]methyl]-3,4,6,7,8,9-
hexahydro-2H-pyrimido[1,2-a]pyrimidine Hydroperchlorate 10.
C41H53N3O2Si2‚HClO4 (MW 776.51). HPLC analysis: Rv ) 16 mL,
RP Aqua C18, 250 × 4.60 mm, 5 µm column, UV254 nm, flow )
1 mL/min, gradient from 80% CH3OH to 90% CH3OH in 5 min
and then 90% CH3OH for 10 min more, 0.1% TFA as a buffer.
1
MS-ESI: m/z ) 676.6 [(M + H)+, 100]. H NMR (360 MHz;
CDCl3): δ ) 7.59-7.62 (m, 8H, aromatic), 7.34-7.48 (m, 12H,
aromatic), 6.98 (d, 1H, guanidinium), 6.72 (bs, 1H, guanidinium),
3.49-3.69 (m, 5H, -CH2OSi- + -CHCH2-), 3.42 (m, 1H,
-CHCH2-), 3.07-3.30 (m, 4H, -NCH2-), 1.70-1.97 (m, 4H,
-CHCH2-), 1.05 (2s, 18H, tert-butyl-CH3). 13C NMR (90.56 MHz;
CDCl3): δ ) 150.7 (guanidinium carbon), 135.5, 135.4, 132.6,
132.3, 130.2, 130.2, 128.0, 127.8 (aromatic carbons), 65.2, 63.0
(-CH2OSi-), 57.0, 50.0 (-CHCH2-), 44.3, 35.1 (-NCH2-), 26.7,
26.7 (tert-butyl-CH3), 22.7, 21.5 (-CHCH2-), 19.0, 19.0 (quater-
nary carbons).
(2S,8S)-2,8-Dihydroxymethyl-3,4,6,7,8,9-hexahydro-2H-py-
rimido[1,2-a]pyrimidine Hydrochloride 13. To a solution of the
bicyclic guanidinium iodide 6 (1.0 g, 1.24 mmol) in dry THF (25
mL) were added triethylamine hydrochloride (513 mg, 3.73 mmol)
and fluoride (1.25 g, 3.73 mmol) supported on polymer. The
suspension was stirred at room temperature. In the initial 2 h of
stirring, the reaction mixture became a clear solution with polymer
bits in it. After continued stirring overnight, a precipitation occurred
in the reaction mixture. The precipitate was filtered off, and the
residue was taken up in methanol (15 mL) and stirred vigorously
for 15 min. Filtration separated the product solution from the
polymer, which was repeatedly washed with methanol. The
combined filtrates and washings were evaporated in vacuo to afford
a white solid compound 13 (400 mg) (containing triethylamine
hydrochloride salt). A small sample was purified for analysis using
SPE, and the remainder was used as is in the further reaction without
any purification.
13. C9H17N3O2‚HCl (MW 235.7). HPLC analysis: Rv ) 7 mL,
RP Aqua C18, 250 × 4.60 mm, 5 µm column, UV254, flow ) 1
mL/min, gradient from 10% CH3OH to 50% CH3OH in 10 min
and then to 90% CH3OH in next 10 min, 0.1% TFA as a buffer.
1
MS-ESI: m/z ) 200.4 [(M + H)+, 100]. H NMR (360 MHz;
5-Nitroisophthalic Acid Dichloride 17. To a suspension of
5-nitroisophthalic acid 16 (20 g, 95 mmol) in dry dichloromethane
(120 mL) under nitrogen was added dropwise oxalyl chloride (75
mL, 393 mmol). Then DMF (0.5 mL) was added cautiously to the
reaction mixture. After the reaction mixture was stirred for 22 h at
room temperature, a clear solution was obtained. The evaporation
of excess oxalyl chloride and solvent left a solid residue, which
was recrystallized, from carbon tetrachloride to afford 17 (12 g,
51%) as colorless crystalline substance.
CD3OD): δ ) 3.6-3.7 (m, 2H, -CHCH2-), 3.4-3.5 (m, 4H,
-CH2OH), 3.43-3.41 (m, 4H, -NCH2-), 2.0-2.1 (m, 2H,
-CHCH2-), 1.85-1.80 (m, 2H, -CHCH2-). 13C NMR (90.56
MHz; CD3OD): δ ) 152.4 (guanidinium carbon), 64.9 (-CH2-
OH), 51.6 (-CHCH2), 46.4 (N-CH2-), 23.9 (-CHCH2-).
(2S,8S(-2,8-Dimethylsulfonyloxymethyl-3,4,6,7,8,9-hexahydro-
2H-pyrimido[1,2-a]pyrimidine Hydrochloride 14. The above
reaction residue containing dihydroxymethylguanidinium chloride
13 (400 mg, 1.24 mmol) was suspended in dry dichloromethane
(20 mL) under nitrogen atmosphere. The mixture was cooled to
0 °C in an ice bath, and triethylamine (0.520 mL, 3.72 mmol) was
added. Then the solution of methanesulfonyl chloride (0.560 mL,
7.44 mmol) in dichloromethane (4 mL) was added dropwise. The
17. C8H3Cl2NO4 (MW 248.0). Mp: 60 °C (CCl4) (lit.59 mp 59-
1
61 °C). H NMR (360 MHz; CDCl3): δ ) 9.20 (d, J ) 1.52 Hz,
(59) Baek, J.-B.; Tan, L.-S. (United States Air Force, U.S.A.). Pat. Appl.
US US 2003, 6 pp.
1086 J. Org. Chem., Vol. 73, No. 3, 2008