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Y. Ichikawa et al.
Paper
Synthesis
13C NMR (125 MHz, CDCl3): = 168.3, 163.8, 72.6, 51.6, 28.4, 20.7.
IR (KBr): 3566, 3321, 2949, 2921, 1762, 1683, 1531, 1372, 1216 cm–1
.
HRMS (ESI): m/z calcd for C13H25N2O4 [M + H]+: 273.1809; found:
273.1806.
1H NMR (500 MHz, CDCl3): = 7.10 (d, J = 9.2 Hz, 1 H), 6.95 (d, J = 9.2
Hz, 1 H), 5.65 (s, 1 H), 4.34 (m, 2 H), 2.30 (s, 3 H), 1.90–1.65 (m, 6 H),
1.52–1.16 (m, 4 H), 1.12–0.98 (m, 6 H), 0.96–0.80 (m, 20 H).
N1,N3-Di-tert-butyl-2-hydroxymalonamide (9)
13C NMR (125 MHz, CDCl3): = 168.4, 164.2, 163.6, 72.0, 46.62, 46.58,
46.25, 46.15, 39.8, 34.5, 29.39, 29.32, 26.8, 26.7, 25.28, 25.26, 22.14,
22.12, 21.0, 20.9, 20.70, 20.67, 20.6.
HRMS (ESI): m/z calcd for C25H45N2O4 [M + H]+: 437.3374; found:
437.3367.
A solution of 8 (90 mg, 0.34 mmol), Et3N (0.10 mL), H2O (0.10 mL) and
MeOH (2.0 mL) was stirred at room temperature for 3 h. The solution
was concentrated under reduced pressure, and the resulting residue
(74 mg) was purified by silica gel chromatography (EtOAc/hexane, 1:5
followed by 5:1) to afford 9 as a white solid; yield: 55 mg (71%); mp
122–123 °C (recrystallized from EtOAc/hexane).
2-Hydroxy-N1,N3-bis((1S,2S,5R)-2-isopropyl-5-methylcyclohex-
yl)malonamide (16)
IR (KBr): 3432, 3357, 3277, 3080, 2972, 1653, 1542, 1219, 1116 cm–1
.
1H NMR (500 MHz, pyridine-d5): = 7.70 (br s, 2 H), 7.05 (br, 1 H),
4.77 (s, 1 H), 1.34 (s, 18 H).
1H NMR (500 MHz, CDCl3): = 7.09 (br s, 2 H), 4.65 (d, J = 2.9 Hz, 1 H),
4.23 (d, J = 2.9 Hz, 1 H), 1.36 (s, 18 H).
13C NMR (125 MHz, pyridine-d5): = 169.2, 72.8, 51.1, 28.5.
13C NMR (125 MHz, CDCl3): = 167.7, 70.5, 51.4, 28.4.
To a solution of 15 (129 mg, 0.30 mmol) dissolved in a mixture of H2O
(0.10 mL) and MeOH (2.0 mL) was added Et3N (0.10 mL). The solution
was stirred at room temperature for 3 h and then concentrated under
reduced pressure. The resulting residue (106 mg) was purified by sili-
ca gel chromatography (EtOAc/hexane, 1:5) to afford 16 as a white
solid; yield: 95 mg (81%); mp 101–102 °C (recrystallized from hex-
ane).
HRMS (ESI): m/z calcd for C11H23N2O3 [M + H]+: 231.1701; found:
[]D28 +51.8 (c 1.00, CHCl3).
231.1703.
IR (KBr): 3405, 3349, 2959, 2923, 1671, 1516, 1116 cm–1
.
1H NMR (500 MHz, pyridine-d5): = 7.98 (d, J = 9.2 Hz, 1 H), 7.83 (d,
J = 9.8 Hz, 1 H), 7.69 (br s, 1 H), 5.12 (s, 1 H), 4.63–4.54 (m, 2 H), 1.93–
1.88 (m, 2 H), 1.73–1.61 (m, 2 H), 1.60–1.38 (m, 5 H), 1.35–1.27 (m, 1
H), 1.14–0.89 (m, 5 H), 0.99 (d, J = 6.3 Hz, 3 H), 0.97 (d, J = 6.3 Hz, 3 H),
0.87 (d, J = 6.9 Hz, 3 H), 0.83–0.71 (m, 3 H), 0.82 (d, J = 6.9 Hz, 3 H),
0.77 (d, J = 6.3 Hz, 3 H), 0.75 (d, J = 6.9 Hz, 3 H).
1H NMR (500 MHz, CDCl3): = 7.51 (d, J = 8.5 Hz, 1 H), 7.41 (d, J = 9.2
Hz, 1 H), 4.64 (d, J = 2.3 Hz, 1 H), 4.45 (d, J = 2.3 Hz, 1 H), 4.36–4.29 (m,
2 H), 1.90–1.73 (m, 6 H), 1.52–1.40 (m, 2 H), 1.32–1.21 (m, 2 H), 1.12–
1.00 (m, 6 H), 0.97–0.83 (m, 20 H).
2-Hydroxy-N-((1S,2S,5R)-2-isopropyl-5-methylcyclohexyl)acet-
amide (13)
TFA (0.20 mL, 2.67 mmol) was added to a solution of isocyanide 12
(250 mg, 1.50 mmol), aqueous formaldehyde (37%, 0.58 mL) and pyri-
dine (0.72 mL, 9.8 mmol) in CH2Cl2 (4.0 mL) at 0 °C. After stirring at
0 °C for 4 h, the cooling bath was removed, and stirring was continued
for 4 h. Concentration of the reaction mixture under reduced pressure
afforded a residue (973 mg), which was purified by silica gel chroma-
tography (EtOAc/hexane, 1:1) to afford 13 as a white solid; yield: 309
mg (97%); mp 71–72 °C (recrystallized from hexane).
13C NMR (125 MHz, pyridine-d5): = 169.5, 168.7, 72.4, 46.64, 46.57,
46.49, 46.35, 40.4, 34.9, 29.62, 29.61, 26.91, 26.87, 25.5, 25.4, 22.4,
21.18, 21.06, 21.00, 20.95.
[]D30 +35.5 (c 1.00, CHCl3).
IR (KBr): 3395, 3296, 2958, 2925, 1656, 1535, 1081 cm–1
.
1H NMR (500 MHz, CDCl3): = 6.85–6.75 (br, 1 H), 4.40–4.34 (m, 1 H),
4.07 (s, 2 H), 3.50–2.50 (br, 1 H), 1.88–1.80 (m, 2 H), 1.78–1.72 (m, 1
H), 1.52–1.40 (m, 1 H), 1.38–1.27 (m, 1 H), 1.13–1.03 (m, 3 H), 1.00–
0.80 (m, 10 H).
13C NMR (125 MHz, CDCl3): = 168.1, 167.5, 70.2, 46.8, 46.6, 46.3,
46.2, 40.0, 34.6, 29.4, 29.3, 26.7, 26.6, 25.2, 22.2, 21.0, 20.9, 20.7, 20.6.
HRMS (ESI): m/z calcd for C23H43N2O3 [M + H]+: 395.3268; found:
395.3263.
13C NMR (125 MHz, CDCl3): = 171.7, 62.0, 46.1, 45.7, 40.0, 34.6, 29.4,
26.7, 25.2, 22.1, 20.9, 20.7.
HRMS (ESI): m/z calcd for C12H24NO2 [M + H]+: 214.1800; found:
214.1802.
Funding Information
We are grateful for the financial support provided by a Grant-in-Aid
for Scientific Research (C) (16K01916) from the Ministry of Educa-
1,3-Bis((1S,2S,5R)-2-isopropyl-5-methylcyclohexylamino)-1,3-di-
oxopropan-2-yl Acetate (15)
tion, Culture, Sports, Science and Technology (MEXT).
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To a suspension of IBX (291 mg, 1.04 mmol) in THF (5.0 mL) was add-
ed successively AcOH (0.18 mL, 3.12 mmol), -hydroxy acetamide 13
(111 mg, 0.52 mmol) and isocyanide 12 (120 mg, 0.73 mmol). After
stirring at 40 °C for 24 h, the reaction mixture was diluted with Et2O
(7.0 mL) and filtered through Celite. The filtrate was poured into
aqueous NaHCO3. After stirring for 20 min, the aqueous layer was sep-
arated and extracted with Et2O. The combined organic layer was
washed with H2O and brine, and dried (Na2SO4). Concentration under
reduced pressure afforded a residue (184 mg), which was purified by
silica gel chromatography (EtOAc/hexane, 1:5) to afford 15 as a white
solid; yield: 142 mg (63%); mp 101–102 °C (recrystallized from hex-
ane).
Supporting Information
Supporting information for this article is available online at
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References
(1) (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 181. (b) Banm, L.;
Riva, R. Org. React. 2005, 65, 1.
(2) Bode, M. L.; Gravestock, D.; Rousseau, A. L. Org. Prep. Proced. Int.
2016, 48, 89.
[]D27 +43.3 (c 1.00, CHCl3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F