The Journal of Organic Chemistry
Article
Flash column chromatography (SiO2, hexanes/ethyl acetate, 9:1 to
cis-3a-Bromo-1-(4-toluenesulfonyl)octahydrobenzo[c]-
isoxazole (4j). O-Allyl-N-tosyl-hydroxylamine 3j (0.141 g, 0.500
mmol) was allowed to react with N-bromoacetamide (75.9 mg, 0.550
mmol) for 5 h according to GP3. Flash column chromatography
(SiO2, dichloromethane/toluene 1:1) afforded 4j as colorless solid.
8:2) afforded 4d as light yellow solid. Yield: 0.246 g (0.413 mmol,
1
83%, dr >98:2); H NMR (500 MHz, CDCl3) δ = 2.47 (s, 3 H, Me),
4.13 (dd, J = 9.6, 8.1 Hz, 1 H, CHHO), 4.16−4.21 (m, 1 H, CHBr),
4.32 (dd, J = 8.0, 6.2 Hz, 1 H, CHHO), 5.11 (d, J = 6.8 Hz, 1 H,
NCH), 5.18 (s, 2 H, CH2Ph), 5.19 (s, 2 H, CH2Ph), 6.97 (d, J = 8.3
Hz, 1 H), 7.05 (dd, J = 8.3, 2.0 Hz, 1 H), 7.13 (d, J = 2.0 Hz, 1 H),
7.31−7.51 (m, 12 H, Ar−H), 7.28−7.31 (m, 2 H, Ar−H) ppm; 13C
NMR (125 MHz, CDCl3) δ = 21.6 (Me), 49.4 (CHBr), 69.8 (NC),
71.1 (CH2Ph), 71.3 (CH2Ph), 75.7 (OCH2), 113.4, 114.8, 119.9,
127.1, 127.4, 127.7, 127.7, 128.3, 128.4, 129.3, 129.7, 130.1, 132.1,
1
Yield: 0.163 g (0.454 mmol, 91%, dr >98:2); H NMR (500 MHz,
CDCl3) δ = 1.50−1.69 (m, 4 H, Cy), 1.95−2.09 (m, 3 H, Cy), 2.23−
2.31 (m, 1 H, Cy), 2.46 (s, 3 H, Me), 3.52 (d, J = 7.9 Hz, 1 H,
CHHO), 3.77 (d, J = 7.9 Hz, 1 H, CHHO), 3.73−3.76 (m, 1 H,
NCH), 7.36−7.38 (m, 2 H, Ar−H), 7.83−7.85 (m, 2 H, Ar−H); 13C
NMR (125 MHz, CDCl3) δ = 19.0, 21.1, 21.7, 24.4, 35.3, 59.8, 64.6,
78.8, 129.6, 129.8, 130.8, 145.4 ppm; IR (Film, cm−1) ν
̃
= 3066 (w),
136.9, 137.1, 145.4, 149.1, 149.3 ppm; IR (Film, cm−1) ν
̃
= 3088 (m),
2940 (s), 2882 (s), 2863 (m), 1923 (w), 1809 (w), 1727 (w), 1597
(m), 1492 (w), 1447 (m), 1361 (s), 1334 (s), 1169 (vs), 1089 (m),
976 (m), 921 (m), 814 (m), 727 (m), 668 (m), 613 (m), 537 (w);
HRMS (ESI) m/z calcd for [C14H18BrNNaO3S]+ 384.0063, found
384.0063. mp 103 °C.
3065 (m), 3032 (m), 1953 (w), 1921 (w), 1876 (w), 1810 (w), 1732
(w), 1596 (s), 1514 (s), 1455 (m), 1413 (m), 1365 (m), 1335 (m),
1264 (m), 1166 (m), 1018 (m), 911 (m), 741 (m), 668 (s), 592 (s),
547 (w); HRMS (ESI) m/z calcd for [C30H28BrNNaO5S]+ 618.0744,
found 618.0763; mp 108 °C.
cis-3a-Bromo-1-(4-toluenesulfonyl)hexahydro-1H-
cyclopenta[c]isoxazole (4k). O-Allyl-N-tosyl-hydroxylamine 3k
(0.134 g, 0.500 mmol) was allowed to react with N-bromoacetamide
(75.9 mg, 0.550 mmol) for 32 h according to GP3. Flash column
chromatography (SiO2, toluene/dichloromethane 6:4) afforded 4k as
colorless oil. Yield: 0.046 g (0.131 mmol, 26%); 1H NMR (500 MHz,
CDCl3) δ = 1.85−1.98 (m, 3 H, Cy), 2.15−2.21 (m, 1 H, Cy), 2.21−
2.36 (m, 2 H, Cy), 2.45 (s, 3 H, Me), 4.02 (d, J = 9.0 Hz, 1 H,
CHHO), 4.27 (d, J = 9.0 Hz, 1 H, CHHO), 4.68 (dd, J = 7.2, 3.5 Hz, 1
H, NCH), 7.35−7.37 (m, 2 H, Ar−H), 7.86−7.87 (m, 2 H, Ar−H);
13C NMR (125 MHz, CDCl3) δ = 21.7, 26.0, 33.8, 43.9, 67.7, 73.9,
cis-4-Bromo-3-(2-tolyl)-2-(4-toluenesulfonyl)isoxazolidine
(4f). O-Allyl-N-tosyl-hydroxylamine 3f (0.159 g, 0.500 mmol) was
allowed to react with N-bromoacetamide (75.9 mg, 0.550 mmol) for
49 h according to GP3. Flash column chromatography (SiO2, toluene/
dichloromethane 6:4) afforded 4f as colorless solid. Yield: 0.129 g
(0.325 mmol, 65%, dr >98:2); 1H NMR (500 MHz, CDCl3) δ = 2.39
(s, 3 H, Me), 2.46 (s, 3 H, Me), 4.30 (dd, J = 9.6, 2.5 Hz, 1 H,
CHHO), 4.77 (dd, J = 9.6, 4.8 Hz, 1H, CHHO), 5.04 (ddd, J = 6.4,
4.8, 2.5 Hz, 1H, CHBr), 5.70 (d, J = 6.5 Hz, 1 H, NCH), 7.17−7.19
(m, 3 H, Ar−H), 7.37−7.39 (m, 2 H, Ar−H), 7.58−7.60 (m, 1 H, Ar−
H), 7.88−7.90 (m, 2 H, Ar−H) ppm; 13C NMR (125 MHz, CDCl3) δ
= 19.8 (Me), 21.7 (Me), 51.3 (CHBr), 62.5 (NC), 77.8 (OCH2),
125.9, 127.3, 128.2, 129.3, 129.8, 130.1, 132.5, 124.8, 135.5, 145.5
81.1, 129.3, 129.8, 132.3, 145.3 ppm; IR (Film, cm−1) ν
̃
= 3066 (w),
3031 (w), 2963 (s), 2926 (m), 2874 (m), 1726 (w), 1597 (m), 1493
(w), 1448 (m), 1362 (s), 1338 (s), 1165 (vs), 1091 (m), 922 (m), 815
(m), 739 (m), 717 (m), 672 (m), 552 (m), 534 (m); HRMS (ESI) m/
z calcd for [C13H16BrNNaO3S]+ 369.9906, found 369.9907.
ppm; IR (Film, cm−1) ν
̃
= 3099 (m), 3061 (m), 3033 (w), 2925 (m),
2882 (w), 1918 (w), 1810 (w), 1735 (w), 1653 (w), 1596 (m), 1491
(m), 1469 (m), 1342 (s), 1165 (vs), 1089 (m), 1006 (m), 976 (w),
907 (w), 815 (w), 750 (m), 675 (s), 554 (m); HRMS (ESI) m/z calcd
for [C17H18BrNNaO3S]+ 418.0083, found 418.0080; mp 194 °C.
4-Bromo-3,3-dimethyl-2-(4-toluenesulfonyl)isoxazolidine
(4g). O-Allyl-N-tosyl-hydroxylamine 3g (0.128 g, 0.500 mmol) was
allowed to react with N-bromoacetamide (75.9 mg, 0.550 mmol) for 2
h according to GP3. Flash column chromatography (SiO2, hexanes/
ethyl acetate 9:1) afforded 4g as colorless solid. Yield: 0.140 g (0.418
mmol, 84%); 1H NMR (500 MHz, CDCl3) δ = 1.49 (s, 3 H, Me), 1.79
(s, 3 H, Me), 2.44 (s, 3 H, Ar−Me), 4.01 (t, J = 7.9 Hz, 1 H, CHBr),
4.59 (t, J = 8.3 Hz, 1 H, CHHO), 4.70 (t, J = 8.2 Hz, 1 H, CHHO),
7.32−7.34 (m, 2 H, Ar−H), 7.82−7.84 (m, 2 H, Ar−H); 13C NMR
(125 MHz, CDCl3) δ = 21.7 (Me), 22.3 (Me), 25.3 (Me), 51.3
(CHBr), 69.6 (NC), 75.2 (OCH2), 129.0, 129.5, 134.7, 144.9 ppm; IR
(E)-N-Bromo-N-[(3-(4-nitrophenyl)allyl)oxy]-4-toluenesulfo-
namide (5). To a solution of O-allyl-N-tosyl-hydroxylamine 3e (50.0
mg, 0.144 mmol) in CDCl3 (1.0 mL) protected from light N-
bromoacetamide (19.8 mg, 0.144 mmol) was added in one portion.
The solution was stirred at rt for 10 min and then rapidly (contact
time <1 min) filtered over a small plug (SiO2, CDCl3) to afford
unstable (decomposition upon light exposure and evaporation of the
solvent observed) 5 as light yellow solution in CDCl3: 1H NMR (400
MHz, CDCl3) δ = 2.45 (s, 3 H, Me), 4.52 (dd, J = 6.7, 1.1 Hz, 2 H,
CH2O), 6.25 (td, J = 15.9, 6.7 Hz, 1 H, PhCHCH), 6.66 (d, J
= 16.0 Hz, 1 H, PhCHCH), 7.37−7.39 (m, 2 H, Ar−H),
7.46−7.48 (m, 2 H, Ar−H), 7.91−7.93 (m, 2 H, Ar−H), 8.18−8.20
(m, 2 H, Ar−H) ppm; 13C NMR (100 MHz, CDCl3) δ = 21.8, 75.8,
124.0, 125.9, 127.3, 127.9, 129.7, 131.1, 133.9, 142.1, 146.6, 147.4
(Film, cm−1) ν
̃
= 3066 (m), 2988 (m), 2942 (m), 2895 (m), 1919 (w),
ppm; IR (Film, cm−1) ν
̃
= 3106 (w), 3076 (w), 2927 (w), 2856 (w),
2449 (w), 2257 (w), 1922 (w), 1792 (w), 1732 (w), 1596 (m), 1517
(s), 1363 (s), 1344 (s), 1171 (vs), 1188 (m) 1110 (m), 1087 (m), 957
(m), 861 (m), 815 (m), 743 (m), 661 (w), 567 (m).
1807 (w), 1733 (w), 1646 (w), 1597 (m), 1493 (m), 1464 (m), 1332
(s), 1166 (vs), 1157 (vs), 1089 (m), 925 (w), 839 (w), 813 (w), 672
(s), 567 (m), 548 (w); HRMS (ESI) m/z calcd for
[C12H16BrNNaO3S]+ 355.9929, found 355.9937; mp 59 °C.
N-(trans-2-Bromo-3-hydroxy-1-phenylpropyl)-4-toluenesul-
fonamide (6). A suspension of isoxazolidine 4a (0.375 g, 0.980
mmol) and palladium on charcoal (10% Pd, 0.104 g, 977 μmol) in
methanol (9.8 mL) was stirred at rt in an atmosphere of hydrogen (1
atm) for 2 d. After reaction completion, as indicated by TLC analysis,
the reaction mixture was filtered over Celite, and the resulting solution
was concentrated to dryness. Flash column chromatography of the
crude product (SiO2, dichloromethane/ethyl acetate 9:1) afforded 6 as
trans-4-Bromo-3-propyl-2-(4-toluenesulfonyl)isoxazolidine
(4h). O-Allyl-N-tosyl-hydroxylamine 3h (0.135 g, 0.500 mmol) was
allowed to react with N-bromoacetamide (75.9 mg, 0.550 mmol) for
20 h according to GP3. Flash column chromatography (SiO2, toluene/
dichloromethane 1:1) afforded 4h as colorless solid. Yield: 0.121 g
(0.348 mmol, 70%, dr >98:2); 1H NMR (500 MHz, CDCl3) δ = 0.99
(t, J = 7.3 Hz, 3 H, CH3CH2CH2), 1.52−1.60 (m, 2 H, CH3CH2CH2),
1.75−1.80 (m, 2 H, CH3CH2CH2), 2.45 (s, 3 H, Ar−Me), 4.03−4.08
(m, 2 H, CHBr and CHHO), 4.18−4.25 (m, 2 H, NCH and CHHO),
7.34−7.37 (m, 2 H, Ar−H), 7.85−7.87 (m, 2 H, Ar−H); 13C NMR
(125 MHz, CDCl3) δ = 13.8 (CH3CH2CH2), 19.3 (CH3CH2CH2),
21.7 (Ar−Me), 36.5 (CH3CH2CH2), 46.1 (CHBr), 67.4 (NC), 75.8
1
colorless solid. Yield: 0.368 g (0.958 mmol, 98%); H NMR (500
MHz, CDCl3) δ = 2.35 (s, 3 H, Me), 2.60 (t, J = 6.7 Hz, 1 H, OH),
3.71−3.77 (m, 1 H, CHHO), 4.01 (ddd, J = 12.6, 5.7, 4.2 Hz, 1 H,
CHHO), 4.29 (td, J = 6.5, 4.4 Hz, 1 H, CHBr), 4.74 (dd, J = 8.6, 6.6
Hz, 1 H, NCH), 5.78 (d, J = 8.7 Hz, 1 H, NH), 7.02−7.22 (m, 7 H,
Ar−H), 7.53−7.55 (m, 2 H, Ar−H); 13C NMR (125 MHz, CDCl3) δ
= 21.5 (Me), 57.8 (CHBr), 59.8 (NCH), 63.6 (CH2O), 127.1, 128.2,
(OCH2), 129.2, 129.7, 132.6, 145.2 ppm; IR (Film, cm−1) ν
̃
= 3066
(m), 3032 (m), 2960 (s), 2933 (s), 2873 (s), 2736 (w), 2587 (w),
1921 (w), 1806 (w), 1732 (w), 1652 (w), 1597 (s), 1493 (m), 1458
(m), 1362 (s), 1335 (s), 1166 (vs), 1088 (m), 975 (m), 906 (m), 815
(m), 670 (s), 576 (m), 539 (w); HRMS (ESI) m/z calcd for
[C13H18BrNNaO3S]+ 372.0063, found 372.0064; mp 53 °C.
128.4, 129.4, 137.0, 143.5 ppm; IR (Film, cm−1) ν
̃
= 3503 (m), 3275
(m), 3063 (w), 3033 (w), 2925 (w), 2880 (w), 1597 (m), 1495 (w),
1455 (m), 1426 (m), 1323 (s), 1158 (vs), 1092 (m), 1057 (m), 1020
(m), 912 (m), 812 (m), 701 (m), 680 (m), 570 (m), 543 (w); HRMS
H
dx.doi.org/10.1021/jo3026725 | J. Org. Chem. XXXX, XXX, XXX−XXX