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Organic & Biomolecular Chemistry
Page 6 of 13
DOI: 10.1039/C7OB00036G
COMMUNICATION
Journal Name
1334, 1431, 1450, 1469, 1496, 1591, 1651, 2947, 3059 cm-1. m/z 1188, 1260, 1541, 1643, 3335. m/z (APCI) calcd for C10H13ClNO
(APCI) calcd for C16H15N2O2 [M+H]+: 267.1128, found: 267.1130.
[M+H]+: 198.0680, found: 198.0680.
Sodium hydride (60% in oil, 1.0 equiv, 258 mg, 6.45 mmol) was
washed with dry hexane (2 x 10 mL) and the hexane was removed.
Preparation of 1,4-dibenzylpiperazine-2,5-dione 8 [R=CH2Ph]
To a solution of benzylamine 13 (1.0 equiv, 1.0 g, 9.33 mmol) and Dry THF (20 mL) was added to the sodium hydride and cooled down
triethylamine (1.1 eq, 1.43 mL, 10.27 mmol) in DCM (30 mL) was to 0 °C and a solution of 18 (1.0 equiv, 1.275 g, 6.45 mmol) in dry
slowly added chloroacetyl chloride (1.1 equiv, 0.82 mL, 10.27 THF (30 mL) was slowly added.
mmol).
After addition, the mixture was stirred at RT for 45 min and mixture was quenched with water (30 ml) and extracted with DCM
quenched with water (20 mL) and extracted with DCM (3 x 20 mL). (4 x 30 ml). The combined organic phases were concentrated at
The combined organic phases were washed with hydrochloric acid Büchi. The crude product was dissolved into DCM and purified by
(2M, 20 mL) and with a saturated solution of NaHCO3 (20 mL). column chromatography on silica gel using DCM/MeOH (98%/2%).
The resulting mixture was stirred from 0 °C to RT for 17 h. The
The organic phase was dried over Na2SO4, filtered and concentrated 1,4-diphenethylpiperazine-2,5-dione 9 was obtained as a beige solid
to afford the product N-benzyl-2-chloroacetamide 17 as a yellow (588 mg, 1.82 mmol, 56.4%). M.Pt.: 205-207 °C (lit. 210 °C).37 ꢄH
solid (1.380 g, 7.52 mmol, 80.5%). M.Pt: 87-90 °C (lit. 91-92 °C).34 ꢄH (400 MHz, CDCl3): 2.88 (4H, t, J = 7.6 Hz, CH2), 3.60 (4H, t, J = 7.6 Hz,
(400 MHz, CDCl3): 4.12 (2H, s, CH2), 4.50 (2H, d, J = 5.6 Hz, CH2), 6.87 CH2), 3.78 (4H, s, CH2), 7.19 (4H, m, ArH), 7.24 (2H, m, ArH), 7.31
(1H, bs, NH), 7.38-7.29 (5H, m, ArH). ꢄC (100MHz, CDCl3): 42.7, 44.0, (4H, m, ArH). ꢄC (100MHz, CDCl3): 33.3, 48.1, 50.9, 127.0, 128.8,
127.9, 127.9, 129, 137.3, 165.9. IR (NEAT) ν = 723, 744, 783, 1060, 128.9, 138.1, 163.5. IR (NEAT) ν = 696, 739, 1169, 1244, 1298, 1339,
1234, 1550, 1645, 3275. m/z (APCI) calcd for C9H11ClNO [M+H]+: 1429, 1485, 1643, 2938. m/z (APCI) calcd for C20H23N2O2 [M+H]+:
184.0524, found: 184.0524.
323.1754, found: 323.1758.
Sodium hydride (60% in oil, 1.1 equiv, 0.33 g, 8.25 mmol) was
washed with dry hexane (2 x 10 mL) and the hexane was removed. Preparation of 1,4-bis(3-phenylpropyl)piperazine-2,5-dione 10 [R =
Dry THF (15 mL) was added to the sodium hydride and cooled down (CH2)3Ph]
to 0 °C and a solution of 17 (1.0 equiv, 1.380 g, 7.52 mmol) in dry To a solution of 3-phenylpropan-1-amine 15 (1.0 equiv, 1.0 g, 7.40
THF (25 mL) was slowly added.
mmol) and triethylamine (1.1 equiv, 1.14 mL, 8.12 mmol) in DCM
The resulting mixture was stirred from 0 °C to RT for 17 h. The (30 mL) was slowly added chloroacetyl chloride (1.1 equiv, 0.65 mL,
mixture was quenched with water (50 ml). The non-soluble solid in 8.12 mmol). After addition, the mixture was stirred at RT for 30 min
water was filtered and the filtrate was extracted with DCM (2 x 30 and quenched with water (20 mL) and extracted with DCM (3 x 20
ml). The combined organic phases and solid previously filtered were mL). The combined organic phases were washed with a 2M solution
concentrated at Büchi. The crude product was dissolved into DCM of HCl in water (20 mL) and with a saturated solution of NaHCO3 (20
and purified by column chromatography on silica gel using mL). The organic phase was dried over Na2SO4, filtered and
DCM/MeOH (97%/3%).
concentrated
to
afford
the
product
2-chloro-N-(3-
1,4-Dibenzylpiperazine-2,5-dione 8 was obtained as an off-white phenylpropyl)acetamide 19 as an orange oil (1.167 g, 5.51 mmol,
solid (0.476 g, 1.62 mmol, 43%). M.Pt: 94-95 °C (lit. 95-97 °C).35 ꢄH 74.5%). ꢄH (400 MHz, CDCl3): 1.90 (2H, qu, J = 7.6 Hz, CH2), 2.68 (2H,
(400 MHz, CDCl3): 3.96 (4H, s, CH2), 4.58 (4H, s, CH2), 7.28-7.26 (4H, t, J = 7.6 Hz, CH2), 3.50 (2H, q, J = 6.0 Hz, CH2), 4.02 (2H, s, CH2), 6.56
m, ArH), 7.37-7.31 (6H, m, ArH). ꢄC (100MHz, CDCl3): 49.3, 49.4, (1H, bs, NH), 7.20 (3H, m, ArH), 7.30 (2H, m, ArH). ꢄC (100MHz,
128.3, 128.7, 129.1, 135.1, 163.4. IR (NEAT) ν = 717, 933, 1065, CDCl3): 30.9, 33.3, 39.6, 42.8, 126.3, 128.5, 128.7, 141.2, 166.0. IR
1160, 1275, 1328, 1483, 1643. m/z (APCI) calcd for C19H19N2O2 (NEAT) ν = 698, 745, 1260, 1537, 1653, 2938, 3292. m/z (APCI) calcd
[M+H]+: 295.1441, found: 295.1442.
for C11H15ClNO [M+H]+: 212.0837, found: 212.0835.
Sodium hydride (60% in oil, 1.0 equiv, 220.5 mg, 5.51 mmol) was
washed with dry hexane (2 x 10 mL) and the hexane was removed.
Dry THF (20 mL) was added to the sodium hydride and cooled down
Preparation of 1,4-diphenethylpiperazine-2,5-dione
(CH2)2Ph]
9 [R =
To a solution of 2-phenylethan-1-amine 14 (1.0 equiv, 1.0 g, 8.25 to 0 °C and a solution of 19 (1.0 equiv, 1.167 g, 5.51 mmol) in dry
mmol) and triethylamine (1.1 equiv, 1.4 mL, 9.08 mmol) in DCM (30 THF (30 mL) was slowly added. The resulting mixture was stirred
mL) was slowly added chloroacetyl chloride (1.1 equiv, 0.73 mL, from 0 °C to RT for 22 h. The mixture was quenched with water (30
9.08 mmol).
After addition, the mixture was stirred at RT for 45 min and phases were concentrated at rotavap. The crude product was
quenched with water (20 mL) and extracted with DCM (3 x 20 mL). dissolved into DCM and purified by column chromatography on
The combined organic phases were washed with hydrochloric acid silica gel using DCM/MeOH (98%/2%). 1,4-bis(3-
(2M, 20 mL) and with a saturated solution of NaHCO3 (20 mL). phenepropyl)piperazine-2,5-dione 10 was obtained as a pale yellow
ml) and extracted with DCM (4 x 30 ml). The combined organic
The organic phase was dried over Na2SO4, filtered and concentrated solid (604 mg, 1.72 mmol, 62.6%). M.Pt.: 115-118 °C (no lit. value).
to afford the product 2-chloro-N-phenylacetamide 18 as a brown ꢄH (400 MHz, CDCl3): 1.90 (4H, qt, J = 7.2 Hz, CH2), 2.64 (4H, t, J = 7.6
solid (1.275 g, 6.45 mmol, 78.2%). M.Pt: 60-61 °C (lit. 66-67 °C).36 ꢄH Hz, CH2), 3.42 (4H, t, J = 7.6 Hz, CH2), 3.85 (4H, s, CH2), 7.19 (6H, m,
(400 MHz, CDCl3): 2.85 (2H, t, J = 6.8 Hz, CH2), 3.57 (2H, q, J = 6.8 Hz, ArH), 7.29 (4H, m, ArH). ꢄC (100MHz, CDCl3): 28.1, 33.2, 45.9, 50.1,
CH2), 4.02 (2H, s, CH2), 6.60 (1H, bs, NH), 7.21 (2H, m, ArH), 7.25 126.3, 128.4, 128.6, 141.0, 163.5. IR (NEAT) ν = 608, 694, 723, 754,
(1H, m, ArH), 7.33 (2H, m, ArH). ꢄC (100MHz, CDCl3): 35.6, 41.1, 1024, 1487, 1647, 2932, 3292. m/z (APCI) calcd for C22H27N2O2
42.8, 126.9, 128.9, 138.5, 165.86. IR (NEAT) ν = 696, 750, 1040, [M+H]+: 351.2067, found: 351.2064.
6 | Org. Biomol. Chem., 2015, 00, 1-3
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