10.1002/ejoc.202000294
European Journal of Organic Chemistry
FULL PAPER
in acetonitrile (30 mL) and cooled down to 0 °C. Then acetaldehyde (793.0
mg, 18.0 mmol) and K2CO3 (414.6 mg, 3.00 mmol) were added and the
reaction mixture was left at ambient temperature for 4 h. The reaction
mixture was diluted with EtOAc (100 mL), filtered and concentrated under
reduced pressure. Purification by flash chromatography on silica gel
(Biotage Isolera, gradient heptane/EtOAc from 0% – 75% EtOAc) afforded
the two diastereomers of the desired product, nitrone 54a as a pale yellow
solid [167 mg, 24% yield, dr = 95:5 (high/low)] and nitrone 54b (146 mg,
21%) as a white solid [dr = 93:7 (low/high)].
12.9, 13.0, 21.3, 21.6, 22.4, 22.4, 22.48, 22.50, 26.3 (2-CH3, 3'-H, 2'-H,
cyclopropyl CH), 36.6, 36.7 (C-1'), 78.3, 78.8 (C-1''), 107.4, 107.5 (C-2),
163.4, 164.0 (C-4), 165.5, 165.9 (C-5) ppm; HRMS (ESI-TOF): calcd. for
C12H19NO3 [M + H]+ 226.1443, found 226.1445.
rel-(S)-2-((S)-1-Hydroxybut-3-en-1-yl)-4-isobutyl-2-methyloxazol-5(2H)-
one (57a). According to general procedure 1, nitrone 46a (75.0 mg, 0.31
mmol) was dissolved in THF (3 mL) and the resulting solution was treated
with activated zinc powder (102 mg, 1.55 mmol). After the addition of
NH4Cl (83 mg, 1.55 mmol) in H2O (1.5 mL), the grey suspension was
stirred vigorously for 1 h at r.t. Then the reaction mixture was filtered
through a pad of celite, which was rinsed three times with Et2O. The
combined filtrates were washed with water, the layers were separated, and
the combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo to give to give oxazolone 57a (70 mg, 95%) as
colorless oil; Rt = 1.31 (HPLC); 1H NMR (400 MHz, CDCl3): = 0.99 (2 d,
J = 6.7 Hz, 6H, 3'-H), 1.60 (s, 3H, 2-CH3), 1.90 (bd, J = 4.9 Hz, OH), 2.23–
2.30 (m, 2H, 2''-H), 2.42–2.57 (m, 3H, 1'-H, 2'-H), 3.71–3.77 (m, 1H, 1''-H),
5.13–5.20 (m, 2H, 4''-H), 5.79–5.89 (m, 1H, 3''-H) ppm.
Upper diastereomer 54a: 1H NMR (400 MHz, CDCl3): = 1.37 (d, J = 6.5
Hz, 3H, 2'-H), 1.89 (s, 3H, 2-CH3), 3.04 (bs, 1H, OH), 4.12 (q, J = 6.5 Hz,
1H, 1'-H), 7.41 (ddd, J = 7.6, 4.8, 1.1 Hz, 1H, pyridyl), 7.86 (ddd, J = 7.8,
7.8, 1.9 Hz, 1H, pyridyl), 8.45 (ddd, J = 7.9, 0.9, 0.9 Hz, 1H, pyridyl), 8.86
(ddd, J = 4.8, 1.8, 0.8 Hz, 1H, pyridyl) ppm; 13C NMR (150 MHz, CDCl3):
= 16.5, 18.7 (2-CH3, C-2'), 71.5 (C-1'), 104.6 (C-2), 120.3, 127.9, 136.9
(pyridyl), 143.8 (C-4), 150.2 (pyridyl), 152.1 (C-4), 161.9 (C-5) ppm.
Lower diastereomer 54b: 1H NMR (400 MHz, CDCl3): = 1.42 (d, J = 6.6
Hz, 3H, 2'-H), 1.79 (s, 3H, 2-CH3), 2.50–3.50 (bs, 1H, OH), 4.34 (q, 1H, J
= 6.7 Hz, 1'-H), 7.35 (dd, J = 7.6, 4.8 Hz, 1H, pyridyl), 7.77–7.80 (m, 1H,
pyridyl), 8.33–8.35 (m, 1H, pyridyl), 8.77–8.79 (m, 1H, pyridyl) ppm; 13C
NMR (150 MHz, CDCl3): = low: 17.0, 20.3 (2-CH3, C-2'), 68.9 (C-1'),
106.0 (C-2), 123.9, 125.2, 136.8 (pyridyl) 143.8 (C-4), 145.0 (pyridyl),
162.7 (C-5), ppm; HRMS (ESI-TOF): calcd. for C11H12N2O4 [M + H]+
237.0875, found 237.0876.
rel-(S)-2-((R)-1-Hydroxybut-3-en-1-yl)-4-isobutyl-2-methyloxazol-5(2H)-
one (57b). According to general procedure 1, nitrone 46b (90 mg, 0.37
mmol) was dissolved in THF (3.5 mL) and the resulting solution was
treated with activated zinc powder (122 mg, 1.86 mmol). After the addition
of NH4Cl (100 mg, 1.86 mmol) in H2O (1.75 mL), the grey suspension was
stirred vigorously for 1 h at r.t. Then the reaction mixture was filtered
through a pad of celite, which was rinsed three times with Et2O. The
combined filtrates were washed with water, the layers were separated, and
the combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo to give to give oxazolone 57b (60.0 mg, 68%) as
colorless oil; Rt = 1.26 (HPLC); 1H NMR (400 MHz, CDCl3): = 0.99 (2 d,
J = 6.7 Hz, 6H, 3'-H), 1.59 (s, 3H, 2-CH3), 1.81 (bd, J = 4.9 Hz, 1H, OH),
2.24–2.28 (m, 2H, 2''-H), 2.48 (dd, J = 7.3, 3.0 Hz, 1H), 2.51–2.57 (m, 3H,
1'-H, 2'-H), 3.72 (dd, J = 10.0, 3.0 Hz, 1H, 1''-H), 5.13–5.21 (m, 2H, 4''-H),
5.79–5.89 (m, 1H, 3''-H) ppm; 13C NMR (150 MHz, CDCl3): = 20.5, 22.4
(2-CH3, C-3'), 26.2 (C-2'), 36.1, 36.6 (C-2'', C-1'), 73.6 (C-1''), 106.9 (C-2),
118.8 (C-4''), 133.7 (C-3''), 163.6 (C-4), 165.5 (C-5) ppm; HRMS (ESI-
TOF): calcd. for C12H19NO3 [M + H]+ 226.1443, found 226.1443.
rel-(S)-2-((R)-1-Hydroxypropyl)-4-isobutyl-2-methyloxazol-5(2H)-one
(55b). According to general procedure 1, nitrone 44 (220 mg, 0.96 mmol)
was dissolved in THF (2.5 mL) and the resulting solution was treated with
activated zinc powder (315 mg, 4.82 mmol). After the addition of saturated
NH4Cl solution (2.5 mL), the grey suspension was stirred vigorously for 40
min at r.t. Then the reaction mixture was filtered through a pad of celite,
which was rinsed with Et2O (10 mL). The filtrate was treated with water (15
mL), the layers were separated and the aqueous layer was extracted with
Et2O (3 × 15 mL). The combined organic layers were dried over MgSO4,
filtered and concentrated in vacuo to provide oxazol-5(2H)-one 55b (150
mg, 73%) as colorless oil. Lower diastereomer 55b: Rf = 0.42 (petroleum
1
ether/EtOAc, 2:1); H NMR (400 MHz, CDCl3): = 0.98 (2 d, J = 6.7 Hz,
6H, 3'-H), 1.03 (t, J = 7.4 Hz, 3H, 3''-H), 1.46 (qd, J = 10.3, 7.2 Hz, 1H, 2''-
H), 1.55 (s, 3H, 2-CH3), 1.78 (qdd, J = 10.0, 7.6, 2.5 Hz, 1H, 2''-H), 2.07
(br s, 1H, OH), 2.18 (qqdd, J = 6.8, 6.8, 6.8, 6.8 Hz, 1H, 2'-H), 2.47 (dd, J
= 14.8, 6.9 Hz, 2H, 1'-H), 3.51 (dd, J = 10.3, 2.5 Hz, 1H, 1''-H) ppm; 13C
NMR (100 MHz, CDCl3): = 10.6 (C-3''), 20.3, 22.4, 24.4, 26.2, 36.6 (2-
CH3, C-1', C-2', C-2'', C-3'), 107.7 (C-2), 163.4, 165.5 (C-4, C-5) ppm; The
signal for C-1'' is obscured.
2-(2-Hydroxypropan-2-yl)-4-isobutyl-2-methyloxazol-5(2H)-one
(58).
According to general procedure 1, a solution of nitrone 47 (100 mg, 0.43
mmol) in THF (12 mL) was treated with activated zinc powder (171 mg,
2.61 mmol). After the addition of NH4Cl solution (140 mg, 2.61 mmol, in 6
mL water), the grey suspension was stirred vigorously for 60 min at r.t.
Then the reaction mixture was diluted with EtOAc, filtered through a pad
of celite, which was rinsed with EtOAc several times. The collected organic
phases were extracted with water, dried over Na2SO4, filtered, the filter
cake washed with EtOAc, and concentrated in vacuo to give oxazolone 58
(60.0 mg, 61%, 95% purity) as a colorless oil; Rt = 1.17 (HPLC); 1H NMR
(600 MHz, CDCl3): = 1.00 ("t", J = 6.7 Hz, 6H, 3'-H), 1.29 (s, 3H, 2''-H),
1.33 (s, 3H, 2''-H), 1.61 (s, 3H, 2-CH3), 2.06 (bs, 1H, OH), 2.16–2.22 (m,
1H, 2'-H), 2.49 (d, J = 7.2 Hz, 2H, 1'-H) ppm; 13C NMR (150 MHz, CDCl3):
= 20.8 (2-CH3), 22.4, 22.5, (C-2''), 24.7, 25.0, (C-3'), 26.3 (C-2'), 36.6 (C-
1'), 73.8 (C-1''), 109.3 (C-2), 163.4 (C-4), 165.7 (C-5) ppm; HRMS (ESI-
TOF): calcd. for C11H19NO3 [M + H]+ 214.1443, found 214.1443.
2-(Cyclopropyl(hydroxy)methyl)-4-isobutyl-2-methyloxazol-5(2H)-one (56).
According to general procedure 1, nitrone 45 (560 mg, 2.32 mmol) was
dissolved in THF (17.8 mL) and the resulting solution was treated with
activated zinc powder (910.6 mg, 13.9 mmol). After the addition of NH4Cl
(745 mg, 13.9 mmol) in H2O (8.9 mL), the grey suspension was stirred
vigorously for 1 h at r.t. Then the reaction mixture was filtered through a
pad of celite, which was rinsed three times with EtOAc. The combined
organic filtrates were washed with water, the layers were separated, and
the combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo to give oxazolone 56 (240 mg, 44%) as colorless oil
(isomeric mixture = 58:42) after purification on a diol phase (Chromabond,
Biotage Isolera, gradient heptane/EtOAc, 20mL/min, 3 – 30%EtOAc); Rt =
1.24, 1.25 (HPLC); 1H NMR (400 MHz, CDCl3): = 0.36–0.47 (m, 2H,
cyclopropyl), 0.55–0.75 (m, 2H, cyclopropyl), 0.98–1.01 (m, 6H, 3'-H),
1.02–1.12 (m, 1H, cyclopropyl), 1.66, 1.67 (2 s, 3H, 2-CH3), 2.16–2.25 (m,
1H, 2'-H), 2.46–2.52 (m, 2H, 1'-H), 3.08–3.13 (m, 1H, 1''-H) ppm; 13C NMR
(150 MHz, CDCl3): = (ca 58:42 ratio) 2.1, 2.4, 4.3, 4.5 (cyclopropyl CH2),
rel-(S)-2-((R)-1-Hydroxyethyl)-4-isobutyl-2-isopropyloxazol-5(2H)-one
(59b). According to general procedure 1, nitrone 49b (165 mg, 0.68 mmol)
was dissolved in THF (1.5 mL) and the resulting solution was treated with
activated zinc powder (222 mg, 3.4 mmol). After the addition of saturated
NH4Cl solution (1.5 mL), the grey suspension was stirred vigorously for 40
min at r.t. Then the reaction mixture was filtered through a pad of celite,
which was rinsed with Et2O (10 mL). The filtrate was treated with water (10
mL), the layers were separated and the aqueous layer was extracted with
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