2006
S. Guery et al.
LETTER
(16) Synthesis of Compound 1d:
SS, 100-200 Mesh, 0.7 mmoles/g, 1% DVB (Divinylben-
zene)] was used as the amine component in solid phase
synthesis. Moreover, the use of supported amine reagent
allowed us to avoid a purification step using chromatogra-
phy on silica gel, which was needed in the solution phase
synthesis. Most of the crude products were isolated in
high yields and high purities, except when the indolin-2-
yl carboxylic acid was used (31% yield and 86% purity).
A mixture of 4-aminobutanal diethylacetal (33 mmoles, 1
equiv) and 2,4-dimethoxybenzaldehyde (33 mmoles, 1
equiv) and benzene (90 mL) was heated at 105 °C for 3 h,
using a Dean–Stark trap. The solvent was removed by
evaporation under reduced pressure and the residue was
dissolved in anhyd MeOH (60 mL). NaBH4 (43.8 mmoles,
1.3 equiv) was added in portion to the stirred solution at
10 °C. The reaction was warmed to r.t., stirred for a further
1 h, and quenched with sat. NH4Cl solution. Then, the
mixture was basified with sat. K2CO3 solution and
evaporated under reduced pressure. The residue was
partitioned between water and EtOAc. The organic layer was
washed with brine, dried with sodium sulfate and evaporated
to give 10.9 g of an orange oil (compound 8). Yield: 100%.
1H NMR (300 MHz, CDCl3): = 1.17–1.21 (t, 6 H, J = 7.02
Hz), 1.54–1.65 (m, 4 H), 2.57–2.62 (t, 2 H, J = 6.85 Hz),
3.43–3.53 (m, 2 H), 3.58–3.68 (m, 2 H), 3.71 (s, 2 H), 3.79
(s, 3 H), 3.80 (s, 3 H), 4.46–4.50 (t, 1 H, J = 5.29 Hz), 6.41–
6.45 (m, 2 H), 7.11–7.13 (d, 1 H, J = 7.8 Hz).
In conclusion, we have described here a new and efficient
combination of protective groups for a guanidine moiety.
The resulting masked guanidine is stable in presence of
electrophiles or nucleophiles. Thus, aldehydes bearing
this fully protected guanidine, in particular guanidino
butanal, were used in an Ugi reaction. When performed
in SPS, it constituted an expeditive manner to prepare li-
braries of arginine derivatives.
A mixture of compound 8 (23.9 mmoles, 1 equiv) and pmc-
1H-pyrazole-1-carboxamidine (26.3 mmoles, 1 equiv) in dry
DMF (44 mL) was heated in a sealed tube for 48 h. The
solvent was removed under reduced pressure and the residue
was partitioned between EtOAc and a sat. NH4Cl solution.
The organic layer was washed with brine, dried with Na2SO4
and evaporated. The crude product was purified by
chromatography on silica gel, eluting first with hexane/ethyl
acetate (2/1) and then with hexane/ethyl acetate (1/1) to give
12.09 g of a colorless oil (compound 11). Yield: 82%.
1H NMR (300 MHz, CDCl3): = 1.13–1.18 (t, 6 H, J = 6.96
Hz), 1.30 (s, 6 H), 1.52–1.59 (m, 4 H), 1.77–1.82 (t, 2 H,
J = 6.78 Hz), 2.09 (s, 3 H), 2.53–2.63 (m, 8 H), 3.32–3.44
(m, 4 H), 3.54–3.60 (m, 2 H), 3.77 (s, 6 H), 4.39–4.42 (m, 3
H), 6.34–6.44 (m, 4 H), 6.97–7.00 (d, 1 H, J = 8.67 Hz).
The compound 11 (19.5 mmoles, 1 equiv) was dissolved in
HOAc/H2O (2/1) (240 mL) and the mixture was stirred at r.t.
overnight. The solution was cooled to 0 °C, alkalinised with
sat. K2CO3 solution, and extracted with ethyl acetate. The
organic layer was washed with sat. K2CO3 solution and then
with brine, dried with Na2SO4 and evaporated under reduced
pressure to give 10.6 g of a white foam (compound 1d).
1H NMR (300 MHz, CDCl3): = 1.31 (s, 6 H), 1.78–1.83 (m,
4 H), 2.10 (s, 3 H), 2.40–2.45 (t, 2 H, J = 6.54 Hz), 2.57–2.65
(m, 8 H), 3.30–3.36 (t, 2 H, J = 7.47 Hz), 3.80 (s, 6 H), 4.39
(s, 2 H), 6.36–6.57 (m, 4 H), 7.00–7.03 (d, 1 H, J = 8.4 Hz),
9.64 (s, 1 H).
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