The Journal of Organic Chemistry
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14.1 Hz, 1H), 4.89−4.97 (m, 2H), 5.71 (m, 1H), 7.20−7.22 (m, 2H),
7.25−7.28 (m, 2H), 7.29−7.32 (m, 1H), 7.42 (s, 5H); 13C NMR (100
MHz, CDCl3) δ 23.1, 33.7, 37.7, 59.3, 87.9, 115.0, 127.6, 127.8, 128.4,
128.5, 128.8, 129.0, 135.2, 136.7, 138.4; HRMS (ESI) m/z calcd for
C19H22NO [M + H]+ 280.1701, found 280.1739. Minor diastereomer
(E)-1ad: Rf = 0.45 (5% EtOAc/hexanes, run twice); IR (neat) 2926,
1452 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.43−1.58 (m, 2H), 2.06−
2.16 (m, 2H), 2.19−2.36 (m, 2H), 4.16 (s, 2H), 4.96−5.03 (m, 2H),
5.74 (m, 1H), 7.27−7.34 (m, 4H), 7.35−7.39 (m, 3H), 7.40−7.44 (m,
3H); 13C NMR (100 MHz, CDCl3) δ 24.7, 29.2, 33.8, 58.2, 85.6,
115.6, 126.5, 127.8, 128.5, 128.6, 128.7, 128.8, 136.6, 137.9, 139.1;
HRMS (ESI) m/z calcd for C19H22NO [M + H]+ 280.1701, found
280.1722.
1-(3,4-Dimethoxyphenyl)hex-5-en-1-one 3b. A solution of 3,4-
dimethoxyacetophenone (15.0 g, 83.2 mmol, 1.0 equiv), N,N-
dimethylhydrazine (15.0 g, 249 mmol, 3.0 equiv) and PTSA (0.791
g, 4.16 mmol, 0.050 equiv) in benzene (80 mL) was refluxed for 23 h
under nitrogen atmosphere with removal of water by a Dean−Stark
apparatus. The reaction mixture was concentrated under reduced
pressure, and the residue was purified by vacuum distillation to afford
the corresponding hydrazone as a pale yellow solid in 81% yield (15.0
g, 67.5 mmol). To a cooled 1.0 M LDA solution (9.90 mL, 9.90 mmol,
1.1 equiv) in THF at 0 °C under nitrogen atmosphere was added the
solution of hydrazone (2.00 g, 9.00 mmol, 1.0 equiv) in THF (15 mL)
slowly over 15 min, and it was allowed to stir at 0 °C for 5 h. The
reaction mixture was then cooled to −78 °C, and a solution of 4-
bromo-1-butene (1.45 g, 10.8 mmol, 1.2 equiv) in THF (5 mL) was
added slowly over 10 min. The reaction was warmed to room
temperature and stirred for 18 h. The reaction mixture was
concentrated under reduced pressure, and the residue was diluted
with ether (15 mL) and then treated with an ice-cold solution of dilute
sulfuric acid (15 mL) for 30 min to hydrolyze the hydrazone. The
resulting solution was diluted with water and extracted with ether (2 ×
15 mL), and the combined organic extracts were washed with water (2
× 15 mL) and brine (15 mL), dried over Na2SO4, and concentrated
under reduced pressure. Purification by chromatography on SiO2 (10%
EtOAc in hexanes) afforded the ketone 3b as a white solid (mp 52−54
°C) in 71% yield (1.50 g, 6.41 mmol): Rf = 0.41 (15% EtOAc/hexanes,
run twice); IR (neat) 1672 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.82
(m, 2H), 2.11−2.16 (m, 2H), 2.92 (t, J = 7.3 Hz, 2H), 3.92 (s, 3H),
3.93 (s, 3H), 4.96−5.06 (m, 2H), 5.81 (m, 1H), 6.86 (d, J = 8.3 Hz,
1H), 7.51 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 8.3, 2.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 23.8, 33.4, 37.4, 56.1, 56.2, 110.1, 110.3,
115.4, 122.8, 130.4, 138.2, 149.1, 153.3, 199.0; HRMS (ESI) m/z calcd
for C14H18O3 [M]+ 234.1256, found 234.1236.
3H), 1.24−1.35 (m, 1H), 1.43−1.54 (m, 1H), 1.81 (m, 1H), 1.95−
2.09 (m, 2H), 2.44 (m, 1H), 3.09 (q, J = 6.6 Hz, 1H), 3.92 (s, 3H),
3.94 (s, 3H), 4.89−4.97(m, 2H), 5.71 (m, 1H), 6.93 (d, J = 8.2 Hz,
1H), 6.99 (d, J = 1.9 Hz, 1H), 7.07 (dd, J = 8.2, 2.0 Hz, 1H), 7.22−
7.27 (m, 1H), 7.30−7.36 (m, 4H); 13C NMR (100 MHz, CDCl3) δ
19.2, 23.3, 33.7, 37.8, 56.1, 56.3, 61.4, 88.5, 110.9, 111.2, 115.0, 120.6,
127.1, 127.2, 127.4, 128.6, 138.5, 143.2, 148.7, 149.5; HRMS (ESI) m/
z calcd for C22H28NO3 [M + H]+ 354.2069, found 354.2076.
1-(3,4-Dimethoxyphenyl)-4-hydroxyhex-5-en-1-one 2b. Fol-
lowing the general procedure B, [Cu(PPh3)Cl]4 (51.1 mg, 0.0354
mmol, 0.050 equiv) in THF (12 mL) was reacted with a solution of
oxaziridine 1ba (250 mg, 0.708 mmol, 1.0 equiv) in THF (8 mL). The
reaction mixture was refluxed for 3 h. Purification by chromatography
on SiO2 (3% acetone in CH2Cl2) afforded 85 mg (0.340 mmol, 48%
yield) of the allylic alcohol 2b as a pink oil: Rf = 0.23 (3% acetone in
CH2Cl2); IR (neat) 3435, 1668 cm−1; 1H NMR (400 MHz, CDCl3) δ
1.87−1.96 (m, 1H), 1.99−2.07 (m, 1H), 2.23 (d, J = 4.3 Hz, 1H), 3.08
(t, J = 7.0 Hz, 2H), 3.92 (s, 3H), 3.93 (s, 3H), 4.23 (m, 1H), 5.12 (td,
J = 10.4, 1.4 Hz, 1H), 5.26 (td, J = 17.2, 1.4 Hz, 1H), 5.89 (m, 1H),
6.87 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.60 (dd, J = 8.4, 2.0
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 31.3, 34.0, 56.1, 56.2, 72.4,
110.1, 110.3, 115.0, 123.0, 130.2, 140.9, 149.1, 153.4, 199.3; HRMS
(ESI) m/z calcd for C14H19O4 [M + H]+ 251.1283, found 251.1286.
Ketone 3b was also obtained in 27% yield (45 mg, 0.192 mmol).
(2R,3S)-2-Cyclohexyl-3-(3,4-dimethoxyphenyl)-3-(pent-4′-
en-1′-yl)-1,2-oxaziridine (Z)-1bb and (2S,3S)-2-Cyclohexyl-3-
(3,4-dimethoxyphenyl)-3-(pent-4′-en-1′-yl)-1,2-oxaziridine (E)-
1bb. Following the general procedure A, ketone 3b (0.900 g, 3.84
mmol, 1.0 equiv), cyclohexylamine 4b (0.659 mL, 5.76 mmol, 1.5
equiv), PTSA (36.5 mg, 0.192 mmol, 0.050 equiv), and activated 5 Å
molecular sieves (6.50 g) in toluene (40 mL) were refluxed for 60 h,
followed by oxidation with m-CPBA (0.796 g, 4.61 mmol, 1.2 equiv) in
CH2Cl2 (25 mL). Purification by chromatography on SiO2 (4−6%
EtOAc in hexanes) afforded the major diastereomer (Z)-1bb (0.610 g,
48% yield) as a colorless oil followed by the mixture of 3b and minor
diastereomer (E)-1bb (0.246 g, 19% corrected yield by 1H NMR; (Z)-
1bb:(E)-1bb = ca. 71:29). Subsequent purification of the mixture of
3b and (E)-1bb by chromatography on SiO2 (14% EtOAc in hexanes)
afforded partial separation of (E)-1bb as a colorless oil. Major
diastereomer (Z)-1bb: Rf = 0.33 (10% EtOAc/hexanes, run twice); IR
(neat) 2930, 1450, 1257 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.75−
0.86 (m, 1H), 0.95−1.15 (m, 2H), 1.16−1.32 (m, 3H), 1.39−1.48 (m,
3H), 1.52−1.56 (m, 1H), 1.63−1.70 (m, 2H), 1.72−1.79 (m, 1H),
1.81−1.84 (m, 1H), 1.90−2.04 (m, 2H), 2.31 (m, 1H), 3.86 (s, 3H),
3.87 (s, 3H), 4.85−4.93 (m, 2H), 5.67 (m, 1H), 6.84 (d, J = 8.3 Hz,
1H), 6.86 (d, J = 1.9 Hz, 1H), 6.93 (dd, J = 8.2, 1.9 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 23.2, 24.11, 24.15, 25.8, 28.7, 31.7, 33.7,
38.1, 55.9, 56.1, 60.7, 87.5, 110.7, 110.9, 114.9, 120.3, 127.6, 138.4,
148.5, 149.1; HRMS (ESI) m/z calcd for C20H30NO3 [M + H]+
332.2226, found 332.2223. Minor diastereomer (E)-1bb: Rf = 0.13
(10% EtOAc/hexanes, run twice); IR (neat) 2932, 1452, 1265 cm−1;
1H NMR (400 MHz, CDCl3) δ 1.16−1.36 (m, 3H), 1.41−1.55 (m,
(2R,3S,1′S)-3-(3,4-Dimethoxyphenyl)-3-(pent-4″-en-1″-yl)-2-
(1′-phenylethyl)-1,2-oxaziridi-ne (unlike, cis; 1ba) and
(2S,3R,1′S)-3-(3,4-Dimethoxyphenyl)-3-(pent-4″-en-1″-yl)-2-
(1′-phenylethyl)-1,2-oxaziridine (like, cis; 1ba′). Following the
general procedure A, ketone 3b (1.00 g, 4.27 mmol, 1.0 equiv), (S)-α-
methylbenzylamine 4a (0.815 mL, 6.41 mmol, 1.5 equiv), PTSA (40.6
mg, 0.213 mmol, 0.050 equiv), and activated 4 Å molecular sieves (7.0
g) in toluene (50 mL) were refluxed for 72 h, followed by oxidation
with m-CPBA (0.883 g, 5.12 mmol, 1.2 equiv) in CH2Cl2 (25 mL).
Purification by chromatography on SiO2 (4−6% EtOAc in hexanes)
afforded the major 1ba and the minor 1ba′ diastereomers as a
colorless oil (0.94 g, 62% yield; 1ba:1ba′ = ca. 83:17). A pure sample
of 1ba′ for characterization was obtained during this purification.
Major diastereomer 1ba: Rf = 0.50 (10% EtOAc/hexanes, run twice);
4H), 1.65−1.70 (m, 2H), 1.80−1.84 (m, 2H), 1.95−2.02 (m, 2H),
2.04−2.16 (m, 2H), 2.28 (m, 1H), 2.56 (m, 1H), 3.85 (s, 3H), 3.87 (s,
3H), 4.94−5.01 (m, 2H), 5.73 (m, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.88
(d, J = 1.9 Hz, 1H), 6.93 (dd, J = 8.2, 2.0 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 24.4, 24.6, 24.8, 25.8, 28.9, 29.2, 32.1, 33.8, 56.0, 56.1,
61.4, 85.4, 109.3, 111.1, 115.4, 118.7, 132.5, 138.0, 149.13, 149.15;
HRMS (ESI) m/z calcd for C20H30NO3 [M + H]+ 332.2226, found
332.2224.
Conversion of (Z)-1bb into 2b. Following the general procedure
B, [Cu(PPh3)Cl]4 (21.8 mg, 0.0151 mmol, 0.050 equiv) in THF (7
mL) was reacted with a solution of oxaziridine (Z)-1bb (100 mg,
0.302 mmol, 1.0 equiv) in THF (3 mL). The reaction mixture was
refluxed for 1 h. Purification by chromatography on SiO2
(CH2Cl2:acetone:MeOH, 98.6:1.0:0.4) afforded 28 mg (0.112 mmol,
37% yield) of the allylic alcohol 2b as a pink oil: Rf = 0.12 (35%
EtOAc/hexanes). Ketone 3b was also obtained in 57% yield (40 mg,
0.171 mmol).
1
IR (neat) 1605, 1452, 1257 cm−1; H NMR (400 MHz, CDCl3) δ
1.19−1.31 (m, 1H), 1.40−1.51 (m, 1H), 1.47 (d, J = 6.5 Hz, 3H), 1.70
(m, 1H), 1.90−2.05 (m, 2H), 2.17 (m, 1H), 3.01 (q, J = 6.4 Hz, 1H),
3.62 (br s, 3H), 3.88 (s, 3H), 4.85−4.93(m, 2H), 5.68 (m, 1H), 6.39
(br s, 1H), 6.78 (d, J = 6.5 Hz, 2H), 6.92−6.96 (m, 2H), 7.18−7.24
(m, 3H); 13C NMR (100 MHz, CDCl3) δ 23.1, 23.2, 33.6, 37.9, 55.7,
56.0, 62.7, 88.2, 110.2, 110.8, 114.9, 120.6, 127.4, 127.51, 127.56,
128.3, 138.4, 141.2, 148.1, 149.2; HRMS (ESI) m/z calcd for
C22H28NO3 [M + H]+ 354.2069, found 354.2074. Minor diastereomer
1ba′: Rf = 0.41 (10% EtOAc/hexanes, run twice); IR (neat) 1604,
1453, 1259 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.15 (d, J = 6.6 Hz,
I
dx.doi.org/10.1021/jo3012336 | J. Org. Chem. XXXX, XXX, XXX−XXX