Peptidyl N-Nitrosoanilines
J. Am. Chem. Soc., Vol. 120, No. 15, 1998 3733
until pH 8∼9. The solution was extracted three times with CH2Cl2.
The combined organic phase was washed with water and brine
sequentially and dried over anhydrous MgSO4. The solvent was
evaporated and the residue recrystallized in EtOAc/hexane to yield
p-hydroxyl-N-methylaniline (31) (0.145 g, 78.6%) as a dark brown
solid: 1H NMR (acetone-d6) δ 2.68 (s, 3H), 4.38 (s, 1H), 6.45 (d, 2H,
J ) 9.0 Hz, Ph), 6.63 (d, 2H, J ) 9.0 Hz, Ph), 7.38 (s, 1H); MS calcd
for C7H9NO+ (M+) 123, found 123.
129.4, 128.7, 128.3, 126.5, 120.3, 54.2, 42.7, 37.6, 35.5, 22.1;
HRFABMS calcd for C19
(M + H).
Synthesis of Compound 4. 27: To a stirred solution of N-acetyl-
L-phenylalanine (1 g, 4.83 mmol) and 3-amino-1-propanol vinyl ether
(0.42 mL, 4.83 mmol) in CH2Cl2 (20 mL) was added EDC (0.926 g,
4.83 mmol) and HOBt (0.653 g, 4.83 mmol), with stirring being
continued at 4 °C for 24 h. The reaction mixture was worked up and
dried over anhydrous MgSO4. The solvent was rotary evaporated to
give white solid product 27 (1.1 g, 80%): 1H NMR (CDCl3) δ 1.68
H21ClN4O3 (M+) 388.1302, found 389.1377
1: General Method for Nitrosation Procedure. p-Hydroxyl-N-
methylaniline (31) (0.139 g, 1.13 mmol) was dissolved in 1 mL of
glacial acetic acid in an ice-water bath. Then 5 mL of water and
NaNO2 (0.179 g, 1.14 mmol) were added. The reaction mixture was
stirred for 1 h and quenched by saturated NaHCO3. The resulting
solution was extracted by EtOAc (3 × 20 mL). The combined organic
phase was washed with brine and dried over anhydrous MgSO4. The
solvent was removed to afford 1 (0.130 g, 76%) as a dark brown
solid: 1H NMR (CD3OD) δ 3.22 (s, 3H, CH3), 6.81 (d, 2H, Ph, J )
8.8 Hz), 7.29 (d, 2H, Ph, J ) 8.8 Hz); 13C NMR acetone-d6) 157.73,
122.48, 122.47, 116.74, 32.30; HRMS (CI) calcd for C7H8N2O2 (M+)
152.0586, found 152.0643
(m, 2H, NHCH2CH2), 1.97 (s, 3H, Ac), 2.95 (AB, 1H, CH2Ph, JAB
)
13.2 Hz, JHR-A ) 8 Hz), 3.05 (AB, 1H, CH2Ph, JAB ) 12.2 Hz, JHR-B
) 6 Hz), 3.26 (m, 2H, NHCH2), 3.51 (m, 2H, CH2O), 3.97 (d, 1H, J
) 8.8 Hz, OCHCH2), 4.10 (d, 1H, J ) 8.8 Hz, OCHCH2), 4.55 (d,
1H, J ) 9.2 Hz, HR), 5.87 (s, 1H, NHCH2), 6.22 (d, 1H, J ) 8.0 Hz,
AcNH), 6.35 (q, 1H, J ) 9.2 Hz, OCHCH2), 7.20 (m, 5H); FABMS
calcd for C16H22N2O3 (M+) 290, found 291 (M + H+).
28: To a glacial acetic acid solution (10 mL) of 27 (500 mg, 1.02
mmol) was added 1 N HCl (15 mL) at 0 °C. After being stirred for 10
min, the reaction mixture was immediately quenched by dilution with
60 mL of 30% acetonitrile in H2O. After evaporation of the solvent in
vacuo, the residual oil was redissolved into EtOAc (60 mL), washed
with cold saturated NaHCO3 (2 × 20 mL), and dried over anhydrous
MgSO4. The solvent was removed in vacuo to give white solid product
28 (350 mg, 75%): 1H NMR (CDCl3) δ 1.55 (m, 2H, NHCH2CH2),
1.97 (s, 3H, Ac), 3.01 (AB, 1H, J ) 12.2 Hz, CH2Ph), 3.05 (AB, 1H,
J ) 13.0 Hz, CH2Ph), 3.29 (m, 2H, NHCH2), 3.47 (t, 2H, J ) 6 Hz,
CH2OH), 4.62 (q, 1H, J ) 14.8 Hz, J ) 8.4 Hz, CRH), 6.55 (d, 1H, J
) 8 Hz, AcNH), 7.24 (m, 5H, Ph); MS calcd for C14H20N2O3 (M+)
264, found 265 (M + H+).
30: To a solution of (COCl)2 (0.174 mL, 2 mmoL) in CH2Cl2 (20
mL) was added a mixture of alcohol 28 (500 mg, 1.89 mmol) and
DMSO (0.355 mL, 5 mmol) diluted with CH2Cl2 at -78 °C. The
mixture was added within 5 min, and the reaction solution was stirred
for additional 15 min. The reaction was quenched with 30 mL of water
and extracted with CH2Cl2 (3 × 20 mL). The organic layer was washed
sequentially with 1 N HCl (2 × 10 mL), 1 N NaHCO3 (2 × 10 mL),
and saturated NaCl (2 × 10 mL). The solution was dried over
anhydrous MgSO4. Removal of the solvent in vacuo gave the yellow
syrup which was directly used for reductive amination (340 mg,
72%): 1H NMR (CD3OD) δ 1.57 (m, 2H, NHCH2CH2), 1.83 (s, 3H,
Ac), 2.80 (AB, 1H, CH2Ph, JAB ) 13.2 Hz, JHR-A ) 8 Hz), 2.97 (AB,
1H, CH2Ph, JAB ) 13.2 Hz, JHR-A ) 8 Hz), 3.12 (m, 2H, NCH2), 4.42
(t, 1H, CRH, J ) 8.4 Hz), 6.51 (d, 2H, J ) 6.0 Hz, NPh), 6.55 (d, 2H,
J ) 6.0 Hz, NPh), 7.14 (m, 5H, CH2Ph); FABMS calcd for
C20H25N3O3+ (M+) 355, found 356 (M + H+).
Synthesis of Compound 2. 21: To a stirred solution of N-acetyl-
L-phenylalanine (1 g, 4.83 mmol) and aminoacetaldehyde dimethyl
acetal (0.53 mL, 4.83 mmol) in CH2Cl2 (25 mL) was added EDC (0.926
g, 4.83 mmol) and HOBt (0.653 g, 4.83 mmol), with stirring being
continued at 4 °C for 24 h. The reaction mixture was worked up and
dried over anhydrous MgSO4. The solvent was evaporated to give white
solid product 21 (1.067 g, 75%): 1H NMR (CDCl3) δ 2.00 (s, 3H,
Ac), 3.02 (AB, 1H, CH2Ph, JAB ) 13.6 Hz, JHR-B ) 9.6 Hz), 3.06
(AB, 1H, CH2Ph, JAB ) 13.6 Hz, JHR-A ) 6 Hz), 3.30 (m, 2H, NHCH2),
3.31 (s, 6H, CH(OMe)2), 4.21 (t, 1H, CH(OMe)2), 4.68 (q, 1H, CRH),
6.13 (d, 1H, J ) 7.2 Hz, NHCH2), 6.51 (d, 1H, J ) 8.0 Hz, AcNH),
7.27 (m, 5H, Ph); FABMS calcd for C15H22N2O4 (M+) 294, found 295
(M + H+).
23: Compound 21 (0.5 g, 1.21 mmol) in trifluoroacetic acid (10
mL) was stirred at 0 °C for 10 min. The reaction was immediately
quenched by dilution with 50 mL of 30% CH3CN in H2O. After
evaporation of the solvent in vacuo, the residual oil was redissolved
into EtOAc (60 mL), washed with cold saturated NaHCO3 (2 × 20
mL), and dried over anhydrous MgSO4. The solvent was removed in
vacuo to give yellow oil 23 (0.38 g, 80%): 1H NMR (CD3OD) δ 1.81
(s, 3H, Ac), 2.76 (AB, 1H, CH2Ph, JAB ) 10.6 Hz, JHR-B ) 9.6 Hz),
2.80 (AB, 1H, CH2Ph, JAB ) 13.6 Hz, JHR-A ) 6 Hz), 3.00 (m, 2H,
NHCH2), 4.50 (q, 1H, CRH), 7.16 (m, 5H, Ph); FABMS calcd for
C13H16N2O3 (M+) 248, found 248.
25: General Method for Reductive Amination. To a stirred
solution of 23 (0.2 g, 0.8 mmol) in anhydrous MeOH (20 mL) was
added 4-aminophenol (0.263 g, 2.4 mmol) and NaCNBH3 (0.051 g,
0.8 mmol). After the mixture was stirred at room temperature
overnight, the solvent was removed in vacuo and the residue was
chromatographed with 0-5% MeOH/EtOAc to afford brown solid
product 25 (0.125 g, 50%): 1H NMR (CD3OD) δ 1.83 (s, 3H, Ac),
2.81 (AB, 1H, CH2Ph, JAB ) 13.2 Hz, JHR-A ) 8 Hz), 2.95 (m, 3H),
3.21 (m, 2H, NCH2), 4.43 (t, 1H, CRH, J ) 8.4 Hz), 6.46 (d, 2H, J )
8.8, NPh), 6.55 (d, 2H, J ) 9.2 Hz, NPh), 7.16 (m, 5H, CH2Ph); CIMS
calcd for C19H23N3O3 (M+) 341, found 341.
4: H NMR (300 MHz, acetone-d6) δ 1.58 (m, 2H, NHCH2CH2),
1.84 (s, 3H, Ac), 2.83 (AB, 1H, CH2Ph, JAB ) 11.1 Hz, JHR-A ) 6
Hz), 3.09 (m, 3H), 3.97 (t, 2H, NCH2), 4.54 (m, 1H, CRH), 6.93 (d,
2H, NPh), 7.16 (m, 5H, CH2Ph), 7.36 (d, 2H, NPh), 7.72 (s, 1H,
NHCH2), 7.79 (d, 1H, AcNH), 9.60 (s, 1H, PhOH); 13C NMR (CD3-
OD) 172.00, 169.95, 158.40, 138.98, 130.03, 128.83, 126.99, 123.25,
116.78, 55.40, 42.73, 38.77, 37.27, 27.21, 22.82; HRFABMS calcd
for C20H24N4O4 (M+) 384.1798, found 384.1811.
Synthesis of Compound 5. 22: To a stirred solution of N-acetyl-
L-phenylalanine (1 g, 4.83 mmol) and 4-aminobutyraldehyde diethyl
acetal (0.78 mL, 4.83 mmol) in CH2Cl2 (25 mL) was added EDC (0.926
g, 4.83 mmol) and HOBt (0.653 g, 4.83 mmol), with stirring continued
at 4 °C for 24 h. The reaction mixture was worked up and dried over
anhydrous MgSO4. The solvent was evaporated to give a white solid
product 22 (1.09 g, 70%): 1H NMR (CDCl3) δ 1.19 (t, 2H,
NHCH2CH2), 1.40 (m, 2H, NH(CH2)2CH2), 1.97 (s, 3H, Ac), 2.96 (AB,
1H, CH2Ph, JAB ) 13.6 Hz, JHR-B ) 9.6 Hz), 3.06 (AB, 1H, CH2Ph,
JAB ) 13.6 Hz, JHR-A ) 6 Hz), 3.16 (m, 2H, NHCH2), 3.46 (m, 6H,
CH(OCH2CH3)2), 3.60 (m, 4H, CH(OCH2CH3)2), 4.40 (t, 1H, CH(O-
Et)2), 4.58 (q, 1H, CRH), 5.59 (d, 1H, J ) 7.2 Hz, NHCH2), 6.41 (d,
1H, J ) 8.0 Hz, AcNH), 7.26 (m, 5H, Ph); FABMS calcd for
1
2: H NMR (CD3OD) δ 1.80 (s, 3H, Ac), 2.65 (AB, 1H, CH2Ph,
JAB ) 13.6 Hz, JHR-B ) 9.6 Hz), 2.84 (AB, 1H, CH2Ph, JAB ) 13.6
Hz, JHR-A ) 6 Hz), 3.20 (m, 2H, NCH2), 3.98 (m, 2H, CH2NNO),
4.35 (t, 1H, CRH, J ) 7.6 Hz), 6.80 (d, 2H, NPh, J ) 9.2 Hz), 7.15
(m, 5H, CH2Ph), 7.29 (d, 2H, NPh, J ) 9.2 Hz); 13C NMR (CD3OD)
δ 173.9, 173.0, 158.7, 138.5, 135.2, 130.2, 129.4, 127.7, 123.7, 117.0,
56.1, 45.3, 38.8, 37.2, 22.4; HRFABMS calcd for C19H22N4O4 (M+)
370.1641, found 371.1714 (M + H).
Synthesis of Compound 3. 3: 1H NMR (CD3OD) δ 1.85 (s, 3H,
Ac), 2.79 (AB, 1H, CH2Ph, JAB ) 13.6 Hz, JHR-B ) 9.6 Hz), 2.88
(AB, 1H, CH2Ph, JAB ) 13.6 Hz, JHR-A ) 6 Hz), 3.18 (m, 2H, NCH2),
3.95 (m, 2H, CH2NNO), 4.38 (t, 1H, CRH, J ) 7.6 Hz), 7.17 (m, 5H,
CH2Ph), 7.38 (m, 2H, NPh), 7.15 (m, 5H, CH2Ph), 7.48 (m, 2H, NPh);
13C NMR (20% CDCl3/CD3OD) δ 172.0, 171.0, 139.7, 136.2, 132.9,
+
C19H30N2O4 (M+) 350, found 351 (M + H+).
26: H NMR (CDCl3) δ 1.19 (t, 2H, NHCH2CH2), 1.40 (m, 2H,
NH(CH2)2CH2), 1.97 (s, 3H, Ac), 2.84 (AB, 1H, CH2Ph, JAB ) 13.2
Hz, JHR-A ) 8 Hz), 3.02 (AB, 1H, CH2Ph, JAB ) 13.2 Hz, JHR-A ) 8