Beilstein J. Org. Chem. 2013, 9, 1737–1744.
mixture was stirred for 24 h, then diluted with CH2Cl2 (20 mL) (CH3), 21.6 (CH3), 23.3 (CH3), 23.4 (CHCHCH2CH(CH3)2),
and washed with brine (10 mL). The combined organic phases 23.7 (CH3 ), 24.7 (O=CCHCH2 CH(CH3 )2 ), 29.2
were dried (MgSO4), evaporated in vacuo and purified by flash (NHCHCH(CH3)2), 34.7 (CH2CHCH), 44.0 (CH2CHC=O),
column chromatography (petrol ether/EtOAc 7:3) to give piper- 55.4 (OCH3), 57.2 (NCHC=O), 58.4 (NCHCH), 58.5 (NHCH),
azinone 23 (57 mg, 69%) as a brown solid; mp 152–153 °C; Rf 114.5 (CH arom.), 122.6 (CH arom.), 146.2 (CH arom.), 154.3
0.30 (petrol ether/EtOAc 7:3); IR νmax (thin film): 3209 (br, (CH arom.), 173.9 (C=O); MS (EI+) m/z: 360 (M+, 15%), 303
N-H), 2956 (w, C-H), 1671 (s, C=C), 1622 (s), 1499 (s), 1464 (18%), 192 (100%); HRMS m/z: calcd for C22H36N2O2,
(m), 1442 (m), 1409 (m), 1384 (m), 1366 (m), 1331 (m), 1283 360.2771; found, 360.2774.
(m), 1241 (s), 1180 (m), 1153 (m), 1037 (m), 826 (s), 767 (m)
cm−1; 1H NMR (600 MHz) δ 0.68 (d, J = 6.6, 3H, CH3), 0.79 (3R*,5S*,6R*)-3,5-diisobutyl-6-isopropylpiperazin-2-one
(d, J = 6.6, 3H, CH3), 0.88 (d, J = 6.6, 3H, CH3), 0.93 (d, J = (2): To a solution of piperazinone 25 (320 mg, 0.880 mmol) in
6.5, 3H, CH3), 0.95 (d, J = 6.7, 3H, CH3), 1.07 (d, J = 6.5, 3H, MeCN (10 mL) at 0 °C was added a solution of CAN (2.08 g,
CH3), 1.07 (m, 1H, CH2), 1.55 (m, 1H, CH2), 1.55 (m, 1H, 3.52 mmol) in H2O (10 mL) dropwise over 3 min. The solution
CH(CH3)2), 1.94 (m, 1H, CH(CH3)2), 2.43 (m, 1H, CH(CH3)2), turned from pale yellow to dark orange. The mixture was stirred
3.18 (dd, J = 10.3, 3.6, 1H, CHNH), 3.53 (br. d, J = 12.2, 1H, at 0 °C for 2 h, over which time the solution became light
NCHCH2), 3.76 (s, 3H, OCH3), 5.89 (br. s, 1H, NH), 6.48 (d, J orange. Water (30 mL) was then added and the mixture
= 10.6, 1H, =CH), 6.78 (app. d, J = 8.8, 2H, ArH), 6.89 (app. d, extracted with EtOAc (3 × 20 mL), washed with saturated
J = 8.8, 2H, ArH); 13C NMR (150 MHz) δ 17.9 (CH3), 19.4 aqueous NaHCO3 (40 mL), dried (MgSO4) and evaporated in
(CH3), 20.3 (CH3), 21.5 (CH3), 22.2 (CH3), 23.7 (CH3), 24.1 vacuo to give crude piperazinone that was purified by flash
(CH(CH3)2), 26.4 (CH(CH3)2), 29.0 (CH(CH3)2), 34.4 (CH2), column chromatography (petrol ether/Me2CO 3:2) to give
55.4 (OCH3), 58.0 (CHNH), 58.8 (NCHCH2), 114.3 (CH piperazinone 2 (91 mg, 41%) as a brown oil; Rf 0.53 (petrol
arom.), 122.0 (CH arom.), 129.7 (CH=Cq), 140.0 (Cq=CH), ether/Me2CO 3:2); IR νmax (thin film): 3209 (w, N-H), 2955
143.4 (Cq arom.), 154.3 (Cq arom.), 164.3 (C=O); MS (EI+) m/ (C-H), 1658 (s, C=O), 1467 (m), 1367 (m), 1165 (w), 918 (w),
z: 359 (MH+, 100%), 343 (12%), 192 (13%); HRMS m/z: calcd 722 (w) cm−1; 1H NMR (600 MHz, CDCl3) δ 0.89 (d, J = 6.6,
for C22H35N2O2, 359.2693; found, 359.2678.
3H, C-3CH2CHCH3), 0.90 (d, J = 6.2, 3H, C-5CH2CHCH3),
0.91 (d, J = 5.6, 3H, C-6CHCH3), 0.93 (d, J = 6.9, 3H,
(3R*,5S*,6R*)-3,5-diisobutyl-6-isopropyl-4-(4-meth- C-3CH2CHCH3), 0.94 (d, J = 6.8, 3H, C-5CH2CHCH3), 0.98
oxyphenyl)piperazin-2-one (25): To a solution of piper- (d, J = 6.7, 3H, C-6CHCH3), 1.30 (ddd, J = 13.9, 7.1, 6.5, 1H,
azinone 23 (170 mg, 0.470 mmol) in MeOH (10 mL) was added C-5CH2), 1.33 (ddd, J = 13.9, 8.2, 5.6, 1H, C-5CH2), 1.40 (ddd,
palladium on carbon (50 mg, 10% by weight, 0.047 mmol) and J = 14.2, 10.0, 4.1, 1H, C-3CH2), 1.65 (nonet, J = 6.7, 1H,
the mixture was flushed with hydrogen, then stirred under a C-5CH2CH), 1.74 (m, 1H, C-3CH2CH), 1.88 (ddd, J = 13.7,
hydrogen atmosphere (balloon) at rt. After the piperazinone 10.3, 3.3, 1H, C-3CH2), 1.91 (hepd, J = 6.8, 2.5, 1H, C-6CH),
starting material was consumed (TLC, 4 h) the mixture was 3.06 (dd, J = 6.7, 3.6, 1H, C-6H), 3.15 (dt, J = 7.8, 5.3, 1H,
filtered through celite®, washed with CH2Cl2 (20 mL) and C-5H), 3.40 (dd, J = 10.2, 3.4, 1H, C-3H), 6.22 (brs, 1H, N1H),
evaporated in vacuo to give crude piperazinone that was puri- N4H peak is missing; 13C NMR (125 MHz, CDCl3) δ 17.7
fied by flash column chromatography (petrol ether/Me2CO 4:1) (C-6CHCH3), 21.0 (C-3CH2CHCH3), 21.5 (C-5CH2CHCH3),
to give piperazinone 25 (170 mg, 99%) as a colourless oil; Rf 22.4 (C-6CHCH3), 23.1 and 23.7 (C-3CH2CHCH3/
0.50 (petrol ether/Me2CO 4:1); IR νmax (thin film): 3207 (br, C-5CH2CHCH3), 24.4 (C-3CH2CH), 24.8 (C-5CH2CH), 27.9
N-H), 2954 (m, C-H), 1658 (s, C=O), 1505 (C=C), 1465 (m), (C-6CH), 40.5 (C-5CH2), 41.1 (C-3CH2), 53.3 (C-5), 57.0
1367 (m), 1242 (s), 1180 (m), 1039 (m), 827 (m), 788 (m), 733 (C-3), 59.4 (C-6), 174.2 (C=O); MS (EI+) m/z: 254 (M+, 30%),
(m) cm−1; 1H NMR (600 MHz) δ 0.70 (d, J = 6.5, 3H, CH3), 197 (22%), 169 (43%), 154 (31%); HRMS m/z: calcd for
0.77 (d, J = 6.7, 3H, CH3), 0.90 (d, J = 6.7, 3H, CH3), 0.97 (d, J C15H30N2O, 254.2353; found, 254.2355.
= 6.5, 3H, CH3), 0.98 (d, J = 6.8, 3H, CH3), 1.03 (d, J = 6.5,
3H, CH3), 1.03 (m, 1H, CHCHCH2), 1.55 (m, 1H, CHCHCH2), 1H NMR (600 MHz, DMSO-d6) δ 0.83–0.89 (m, 18H, 6xMe),
1.55 (m, 1H, O=CCHCH2), 1.55 (m, 1H, CHCH(CH3)2), 1.84 1.25 (m, 3H, C-3CH2 + 2xC-5CH2), 1.65 (m, 2H, C-3CH2CH +
(m, 1H, O=CCHCH2), 1.92 (m, 1H, O=CCHCH2CH(CH3)2), C-5CH2CH), 1.79 (m, 2H, C-3CH2 + C-6CH), 2.90 (brd, J =
2.06 (m, 1H, CHCHCH2CH(CH3)2), 3.18 (dd, J = 10.0, 3.5, 3.2, 1H, C-6H), 3.01 (td, J = 7.1, 3.7, 1H, C-5H), 3.21 (dd, J =
1H, NHCH), 3.37 (dt, J = 12.4, 3.1, 1H, NHCHCHN), 3.77 (s, 9.3, 3.2, 1H, C-3H), 7.63 (brs, 1H, NH). Assignments based on
3H, OCH3), 4.09 (dd, J = 9.9, 4.5, 1H, O=CCH), 6.02 (br. s, above; 13C NMR (125 MHz, DMSO-d6) δ 18.4, 21.5, 22.0,
1H, NH), 6.80 (app. d, J = 8.9, 2H, ArH), 6.91 (app. d, J = 8.9, 22.8, 23.0, 23.8, 23.9, 24.2, 27.4, 40.2, 41.5, 53.2, 56.4, 58.1,
2H, ArH); 13C NMR (150 MHz) δ 18.0 (CH3), 19.5 (CH3), 21.5 172.5.
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