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the preparation of 2a. The flask was cooled in an ice
bath for 30 min and then warmed to room temperature
for 2h. The solvent was evaporated and the residue was
recristallized from methanol/ethyl acetate. A white solid
J=9.3 Hz, 2H), 8.29 (d, J=9.3 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d 25.36, 28.54, 31.62, 39.74, 79.62,
122.62, 125.35, 145.47, 155.53, 156.31, 171.02. Mp
120 ꢀC. MS (M+H)+ calcd 325.13995, obtained
325.13890.
1
(2b) was obtained (55 mg, 22%). H NMR (300 MHz,
CD3OD) d 2.19 (m, 2H), 2.75 (t, J=7.1 Hz, 2H), 3.91 (t,
J=6.3 Hz, 1H), 7.31 (d, J=7.9 Hz, 2H), 8.20 (d, J=7.9
Hz, 2H); 13C NMR (100 MHz, DMSO-d6) d 26.68,
30.31, 52.27, 124.28, 126.27, 146.08, 156.31, 170.87,
171.12. Mp 144 ꢀC. MS calcd 268.09335, obtained
268.09460.
4-Aminobutyryl-p-nitrophenyl ester (6). Compound 5
(300 mg, 0.93 mmol) was dissolved in 20 mL of di-
chloromethane. Gaseous HCl, generated by sulphuric
acid (H2SO4) and ammonium chloride (NH4Cl), was
bubbled through the reaction mixture for 1 h. The
solution was filtered and a yellow solid (6) was obtained
(208 mg, 86%). 1H NMR (300 MHz, CD3OD) d 2.05 (q,
J=7.1 Hz, 2H), 2.82 (t, J=7.1 Hz, 2H), 3.06 (t, J=7.7
Hz, 2H), 7.39 (d, J=9.2Hz, 2H), 8.31 (d, J=9.2Hz,
2H). 13C NMR (100 MHz, CD3OD) d 23.50, 31.55,
39.88, 123.89, 126.16, 146.90, 156.86, 171.82. Mp 149–
151 ꢀC. MS (M+) 225.2.
p-Nitrophenyl glutarate (3). Glutaric acid (300 mg, 2.27
mmol) was dissolved in 30 mL acetonitrile. Then, trie-
thylamine (0.23 g, 2.27 mmol), p-nitrophenyl chlor-
oformate (503 mg, 2.50 mmol) and DMAP (28 mg, 0.23
mmol) were added in this order. The reaction was fol-
lowed by thin layer chromatography (59:40:1 ethyl ace-
tate/hexane/acetic acid). At the end of the reaction, the
solvent was evaporated and the residue was dissolved in
chloroform. This solution was washed with distilled
water and the organic phase was partially evaporated
and submitted to flash chromatography (60:40 ethyl
acetate/hexane). The fractions containing the product
were combined and evaporated. A yellow product (3)
was obtained (47 mg, 33%). 1H NMR (300 MHz,
CDCl3) d 2.11 (q, J=7.2 Hz, 2H), 2.56 (t, J=7.1 Hz,
2H), 2.79 (t, J=7.3 Hz, 2H), 7.30 (d, J=9.3 Hz, 2H),
8.29 (d, J=9.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) d
19.68, 32.89, 33.34, 122.59, 125.44, 145.55, 155.45,
170.64, 178.96. Mp 92 ꢀC. MS (M+H)+ 254.1.
4-Carboxybutyramide (7). Glutaric anhydride (500 mg,
4.38 mmol) was dissolved in 10 mL dichloromethane.
Gaseous ammonia (NH3), generated by sodium
hydroxide (NH4OH) and ammonium chloride (NH4Cl),
was bubbled through the reaction mixture until com-
pletion of the reaction (4 days). The reaction mixture
was filtered and the solid thus recovered was washed
with 3Â10 mL of dichloromethane. A white solid (7)
was obtained (190 mg, 34%). 1H NMR (300 MHz,
CD3OD) d 1.88 (q, J=7.3 Hz, 2H), 2.25 (t, J=7.8 Hz,
2H), 2.33 (t, J=7.4 Hz, 2H). 13C NMR (75 MHz,
CD3OD) d 22.12, 34.09, 35.47, 176.86, 178.34. Mp 89–
90 ꢀC. MS (M+H)+ 132.1.
Boc-4-aminobutyric acid (4). 4-Aminobutyric acid (2.00
g, 19.4 mmol) was dissolved in 20 mL methanol. Then,
triethylamine (11.8 g, 116.4 mmol) and di-tert-butyl
dicarbonate (8.89 g, 40.7 mmol) were added and the
flask was heated to 60 ꢀC. The reaction was followed by
TLC (99:1 ethyl acetate/acetic acid) and allowed to
proceed overnight. The solvent was evaporated and the
residual oil was dissolved in saturated sodium bicarbo-
nate (NaHCO3) and extracted with hexane (3Â40 mL).
The aqueous phase was acidified with 1 N HCl to pH 2–
3. The aqueous phase was then extracted with ethyl
acetate (3Â30 mL) and the organic phases were com-
bined and dried over MgSO4. The solvent was evapo-
rated and a white solid (4) was obtained (3.81 g, 97%).
1H NMR (300 MHz, CDCl3) d 1.45 (s, 9H), 1.83 (qu,
J=7.0 Hz, 2H), 2.41 (t, J=7.2 Hz, 2H), 3.19 (m, 2H),
4.70 (br s, 1H); 13C NMR (100 MHz, CDCl3) d 25.03,
28.27, 31.20, 39.69, 79.39, 156.12, 178.32. Mp 58 ꢀC. MS
(M+H)+ calcd 204.12358, obtained 204.12300.
Boc-4-aminobutyramide (8). Compound 5 (350 mg, 1.08
mmol) was dissolved in 20 mL of dichloromethane.
Gaseous ammonia, generated as for the preparation
of 7, was bubbled through the reaction mixture until
completion of the reaction (1 day). The reaction was
followed by TLC (99:1 ethyl acetate/acetic acid). The
solvent was evaporated and the residue was dissolved
in a minimum of chloroform. Flash chromatography
(100% ethyl acetate) was performed and the fractions
containing the product were combined and evapo-
rated. The residue was washed with n-propanol and
dried in vacuo overnight. A yellow solid (8) was
obtained (198 mg, 91%). 1H NMR (300 MHz, CDCl3) d
1.44 (s, 9H), 1.81 (q, J=6.5 Hz, 2H), 2.28 (t, J=7.1 Hz,
2H), 3.19 (t, J=6.4 Hz, 2H), 4.88 (br s, 1H), 5.84 (br s,
1H), 6.41 (br s, 1H); 13C NMR (75 MHz, CDCl3) d
26.22, 28.31, 32.71, 39.60, 79.43, 156.54, 175.41. Mp
125 ꢀC. MS (M+H)+ calcd 203.13957, obtained
203.13870.
Boc-4-aminobutyryl-p-nitrophenyl ester (5). Compound
4 (3.80 g, 18.7 mmol) was dissolved in 75 mL aceto-
nitrile. Triethylamine (2.08 g, 20.6 mmol), p-nitrophenyl
chloroformate (4.15 g, 20.6 mmol) and DMAP (0.23 g,
1.87 mmol) were then added in this order. The reaction
mixture was allowed to sit at room temperature over-
night. The protonated triethylamine was filtered and
discarded. Water was added to the filtrate and a yellow
solid (5) appeared (5.72g, 95%). 1H NMR (300 MHz,
CDCl3) d 1.46 (s, 9H), 1.96 (q, J=6.8 Hz, 2H), 2.67 (t,
J=7.1 Hz, 2H), 3.28 (m, 2H), 4.63 (br s, 1H), 7.31 (d,
4-Aminobutyramide (9). Compound 8 (130 mg, 0.640
mmol) was dissolved in 10 mL chloroform. Gaseous
HCl, generated as for the synthesis of 6, was bubbled
through the reaction mixture for 1 h and allowed to stir
overnight. The reaction was filtered and a yellow solid
1
(9) was obtained (89 mg, 100%). H NMR (300 MHz,
CD3OD) d 1.90 (q, J=7.2 Hz, 2H), 2.37 (t, J=7.1 Hz,
2H), 2.96 (t, J=7.3 Hz, 2H); 13C NMR (100 MHz,
CD3OD) d 24.29, 32.87, 40.29, 178.02. Mp 98–100 ꢀC.
MS (M+H)+ calcd 103.08714, obtained 103.08680.