RESEARCH FRONT
818
P. P. Molesworth et al.
(874 mg, 3.01 mmol) in dry DMF (25 mL), under an atmosphere
of nitrogen, was added cesium carbonate (1.18 g, 3.65 mmol).
After protection from light and stirring for 18 h, the reaction
was quenched with water (20 mL). The precipitated solid was
collected by filtration and washed with t-butyl methyl ether,
yielding the title compound as a yellow solid (919 mg, 61%),
mp 191–192◦C dec. νmax (thin film/cm−1): 748, 1094, 1150,
1227, 1355, 1370, 1441, 1524, 1676, 1705, 1758, 2980, 3201.
δH (CDCl3): 1.76 (m, 9H), 2.66 (s, 3H), 3.27 (ad, J 4.0 Hz, 1H),
5.35 (at, J 4.2 Hz, 1H), 6.76 (s, 1H), 7.05–7.19 (m, 2H), 7.20–
7.31 (m, 3H), 7.46 (t, J 8.2 Hz, 1H), 7.52 (s, 1H), 7.56 (bs, 1H),
7.98 (d, J 8.0 Hz, 1H), 8.57 (d, J 7.9 Hz, 1H). δC (CDCl3): 27.4,
28.3, 39.3, 58.1, 86.6, 113.4, 120.6, 121.3, 121.9, 125.4, 126.0,
127.9, 128.0, 128.8, 128.9, 130.7, 134.5, 138.0, 142.5, 148.7,
160.0, 166.1, 173.2. m/z (EI+): 518 (M+, <1%), 460 (12), 418
(40), 285 (100), 158 (28), 91 (29).
(104 mg, 0.206 mmol) in DMF (5 mL), and stirred for 24 h
protected from light. After quenching with water, the resul-
tant precipitate was collected by filtration, washed with t-butyl
methyl ether, and dried under high vacuum, yielding the title
compound as an orange solid (38 mg, 46%), mp 210–212◦C
dec. νmax (solid/cm−1): 691, 730, 795, 975, 1119, 1252, 1286,
1323, 1377, 1424, 1516, 1615, 1675, 2923, 3027, 3183. δH (d6-
DMSO): 2.64 (s, 3H), 2.90 (s, 3H), 3.05 (dd, J 13.4, 5.1 Hz,
1H), 3.18 (dd, J 13.4, 5.2 Hz, 1H), 4.43 (at, J 5.3 Hz, 1H), 6.87
(s, 1H), 7.06 (s, 1H), 7.11–7.32 (m, 6H), 7.82–7.85 (m, 2H),
12.22 (bs, 1H). δC (d6-DMSO): 33.2, 34.7, 37.8, 64.1, 107.9,
114.3, 118.3, 118.5, 119.5, 121.7, 127.6, 128.8, 129.1, 130.4,
132.0, 136.4, 139.1, 142.3, 161.6, 166.9. m/z (EI+): 404 (M+,
42%), 313 (100), 285 (20), 158 (33), 130 (22). HRMS calc. for
C22H20N4O4 [M+•] 404.14846, found 404.14861.
( )-(6Z)-3-Benzyl-6-[(4-nitro-1H-indol-
3-yl)methylene]piperazine-2,5-dione (13)
( )-(6Z)-3-Benzyl-1,4-dimethyl-6-[(4-nitro-1H-indol-
3-yl)methylene]piperazine-2,5-dione (12)
Hydrazine hydrate (200 µL, 4.16 mmol) was added dropwise to
a solution of 10 (215.9 mg, 0.416 mmol) in DMF (3 mL) and
stirred for 18 h protected from light. The reaction was quenched
with water (15 mL), the precipitated solid collected by filtra-
tion, washed with t-butyl methyl ether and dried under high
vacuum, yielding the title compound as a red solid (131 mg,
84%), mp 285–287◦C dec. νmax (solid/cm−1): 759, 806, 981,
1136, 1209, 1317, 1359, 1435, 1510, 1618, 1659, 3033, 3281.
δH (d6-DMSO): 2.98 (dd, J 13.8, 4.8 Hz, 1H) 3.14 (dd, J 13.5,
3.6 Hz, 1H), 4.30 (m, 1H), 6.61 (s, 1H), 7.03–7.36 (m, 6H),
7.53 (s, 1H), 7.79 (m, 2H), 8.29 (s, 1H), 9.53 (s, 1H), 12.19
(s, 1H). δC (d6-DMSO): 40.1, 56.8, 107.0, 109.4, 118.0, 118.6,
119.0, 121.4, 124.7, 127.3, 128.7, 130.7, 131.6, 136.3, 139.2,
142.6, 160.7, 166.4. m/z (EI+): 376 (M+, 100%), 330 (51), 285
Hydrazine hydrate (62 µL, 1.27 mmol) was added dropwise
to a solution of t-butyl ( )-3-[(Z)-(4-acetyl-5-benzyl-3,6-
dioxo-piperazin-2-ylidene)methyl]-4-nitroindole-1-carboxylate
(657 mg, 1.27 mmol) in DMF (5 mL), protected from light and
stirred for 18 h. The reaction was quenched with water (15 mL),
and the precipitated solid collected by filtration, washed with
t-butyl methyl ether and dried under high vacuum to yield ( )-t-
butyl 3-[(Z)-(5-benzyl-3,6-dioxo-piperazin-2-ylidene)methyl]-
4-nitroindole-1-carboxylate as yellow powder (577 mg, 95%),
mp 187–189◦C dec. Insolubility in common NMR solvents pre-
vented full characterization, the compound was used without
further purification. νmax (solid/cm−1): 697, 743, 790, 1091,
1154, 1278, 1434, 1526, 1634, 1676, 1743, 3069, 3187. m/z
(EI+): 476 (M+, <1%), 376 (100), 330 (54), 285 (78), 158
(48). HRMS calc. for C25H24N4O6 [M+•] 476.16958, found
476.16886.
Iodomethane (1.54 mL, 10.9 mmol) was added to a suspen-
sion of potassium carbonate (1.716 g, 12.4 mmol) and ( )-t-
butyl 3-[(Z)-(5-benzyl-3,6-dioxo-piperazin-2-ylidene)methyl]-
4-nitroindole-1-carboxylate (519 mg, 1.09 mmol) in dry DMF
(15 mL), under an atmosphere of nitrogen. After stirring for 72 h
the reaction was quenched with water (15 mL) and extracted
with ethyl acetate (3 × 15 mL). The combined organic layers
were washed with water (3 × 10 mL), and brine (2 × 25 mL),
dried over magnesium sulfate, filtered and the solvent removed
under reduced pressure. The residue was purified by col-
umn chromatography (60% ethyl acetate/hexanes), yielding
( )-t-butyl 3-[(Z)-(5-benzyl-1,4-dimethyl-3,6-dioxo-piperazin-
2-ylidene)methyl]-4-nitroindole-1-carboxylate as a crystalline
yellow solid (435 mg, 79%), mp 130–132◦C. νmax (thin
film/cm−1): 733, 919, 1101, 1258, 1285, 1315, 1352, 1433,
1522, 1635, 1682, 1743, 2934. δH (CDCl3): 1.71 (s, 9H), 2.76 (s,
3H), 3.05 (s, 3H), 3.20 (d, J 4.7 Hz, 2H), 4.32 (t, J 4.7 Hz, 1H),
6.76 (d, J 1.5 Hz, 1H), 7.04–7.30 (m, 6H), 7.37 (at, J 8.2 Hz, 1H),
7.86 (d, J 8.1 Hz, 1H), 8.45 (d, J 8.4 Hz, 1H). δC (CDCl3): 28.3,
33.4, 34.8, 37.8, 64.6, 86.1, 112.5, 113.1, 120.1, 120.9, 124.5,
127.7, 129.0, 129.2, 130.1, 130.3, 135.2, 137.1, 142.9, 148.7,
160.9, 166.6. m/z (EI+): 504 (M+, <1%), 404 (40), 313 (100),
158 (30). HRMS calc. for C27H28N4O6 [M+•] 504.20088, found
504.19859.
(78), 158 (61), 91 (91). HRMS calc. for C20H16N4O4 [M+•
376.11716, found 376.11747.
]
Methyl (2S)-2-[[2-(t-Butoxycarbonylamino)acetyl]amino]-
3-phenyl-propanoate (N-Boc-Gly-Phe-OMe) (15)
Triethylamine (5.70 mL, 40.9 mmol), then EDAC (7.32 g,
37.6 mmol) were added to a solution of l-phenylalanine methyl
ester (14) (5.62 g, 31.4 mmol) and N-Boc-glycine (6.0887 g,
34.5 mmol) in dry dichloromethane (100 mL), under an atmo-
sphere of nitrogen.The reaction was stirred for 18 h, diluted with
dichloromethane (50 mL), and the organic phase washed with
0.5 M potassium hydrogen sulfate solution (2 × 75 mL) and sat-
urated sodium carbonate solution (1 × 75 mL).The organic layer
was dried with magnesium sulfate and filtered through a plug
of silica gel (eluting with 60% ethyl acetate/hexanes), and the
solvent removed under reduced pressure, to give the title com-
pound as a viscous oil (10.15 g, 96%). δH (CDCl3): 1.40 (s, 9H),
2.95–3.15 (m, 2H), 3.64 (s, 3H), 3.67–3.77 (m, 2H), 4.84 (aq,
J 6.8 Hz, 1H), 5.41 (at, J 5.4 Hz, 1H), 6.85 (bd, J 7.4 Hz, 1H),
7.02–7.09 (m, 2H), 7.14–7.26 (m, 3H). δC (CDCl3): 28.4, 38.1,
44.2, 52.5, 53.3, 80.2, 127.3, 128.7, 129.4, 135.9, 156.2, 169.6,
172.0. m/z (EI+): 336 (M+, <1%), 280 (8), 203 (12), 162 (100),
120 (38). HRMS calc. for C17H24N2O5 [M+•] 336.16852, found
336.16799.
(3S)-3-Benzylpiperazine-2,5-dione (16)
Six batches (2 mL each) of N-Boc-Gly-Phe-OMe (4.67 g,
13.9 mmol), dissolved in ethanol (18.0 mL), were diluted with
water (2 mL) and heated to 160◦C for 1 h in a sealed tube using a
microwave reactor (CEM Discover microwave reactor). The six
Hydrazine hydrate (50 µL, 1.03 mmol) was added to a
solution of ( )-t-butyl 3-[(Z)-(5-benzyl-1,4-dimethyl-3,6-
dioxo-piperazin-2-ylidene)methyl]-4-nitroindole-1-carboxylate