The Journal of Organic Chemistry
Note
Scheme 4. Straightforward Synthesis of Brittonin A
Ozonide 2. Ozonide 2 was obtained (68% yield) from commercial
2-allylphenyl acetate as a colorless oil: IR (film) νmax 1211, 1370, 1492,
1766, 2894 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.35 (dd, J = 7.7, 1.2
Hz, 1H), 7.31 (dt, J = 8.1, 2.0 Hz, 1H), 7.22 (dt, J = 7.7, 1.2 Hz, 1H);
7.12 (dd, J = 8.1, 1.2 Hz, 1H), 5.39 (t, J = 4.5 Hz, 1H), 5.09 (br s, 1H),
5.04 (br s, 1H), 3.05 (dd, J = 14.0, 4.1 Hz, 1H), 2.98 (dd, J = 14.0, 4.0
Hz, 1H), 2.33 (s, 3H); 13C NMR (75 MHz, CDCl3, DEPT) δ 169.2
(C), 149.3 (C), 131.7 (CH), 128.3 (CH), 126.7 (C), 126.0 (CH),
122.6 (CH), 102.5 (CH), 94.0 (CH2), 32.9 (CH2), 20.8 (CH3);
HRMS (EI) m/z calcd for C11H12O5 [M]+ 224.0685, found 224.0714.
Ozonide 3. Commercial 1-allyl-4-methoxybenzene was ozonized to
3 (80%): colorless oil; IR (film) νmax 1033, 1100, 1253, 1514, 1612,
2904 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.23 (d, J = 8.5 Hz, 2H),
6.91 (d, J = 8.8 Hz, 2H), 5.35 (t, J = 4.8 Hz, 1H), 5.18 (br s, 1H), 5.08
(br s, 1H), 3.82 (s, 3H), 3.02 (d, J = 4.8 Hz, 2H); 13C NMR (75 MHz,
CDCl3, DEPT) δ 158.7 (C), 130.7 (CH), 126.5 (C), 113.9 (CH),
103.7 (CH), 94.1 (CH2), 55.1 (CH3), 37.3 (CH2); HRMS (EI) m/z
calcd for C10H12O4 [M]+ 196.0736, found 196.0734.
(1-6) (1 mmol) in THF (2 mL) was then added and the mixture was
stirred for 30 min. Et2O (20 mL) was added and the solution washed
with 2 N HCl and brine. The organic layer was dried over anhyd
Na2SO4 and the solvent removed. Flash chromatography (hexane/t-
BuOMe mixtures) of the residue furnished products 9−14 and 19−24
in yields summarized in Table 1 (SC column).
Dimer 9. Colorless oil: IR (film) νmax 750, 1029, 1446, 1497, 1599,
2897, 3434; 1H NMR (300 MHz, CDCl3) δ 7.60−6.80 (m, 18H), 5.08
(s, 4H), 3.07 (s, 4H); 13C NMR (75 MHz, CDCl3, DEPT) δ 156.6
(C), 137.6 (C), 131.1 (C), 130.2 (CH), 128.4 (CH), 127.6 (CH),
127.1 (CH), 126.9 (CH), 120.6 (CH), 111.6 (CH), 69.7 (CH2); 30.9
(CH2); HRMS (EI) m/z calcd for C28H26O2 [M]+ 394.1933, found
394.1943.
Dimer 14. Colorless oil: IR (film) νmax 809, 1130, 1278, 1503, 1593,
2955, 3435 cm−1; 1H NMR (300 MHz, CDCl3) δ; 7.43 (d, J = 8.5 Hz,
2H), 6.93 (d, J = 8.5 Hz, 2H), 3.84 (s, 3H), 0.65 (s, 2H), 0.24 (s,
6H),13C NMR (75 MHz, CDCl3, DEPT) δ 160.2 (C), 135.1 (CH),
130.2 (C), 113.4 (CH), 55.0 (CH3), 8.0 (CH2), −3.4 (CH3); HRMS
(EI) m/z calcd for C20H30O2Si2 [M]+ 358.1784, found 358.1797.
General Procedure for Ti-Promoted Cross-Coupling of
Ozonides with Olefin 8. Deoxygenated THF (20 mL) was added
to a mixture of Cp2TiCl2 (743 mg, 3 mmol) and Mn dust (439 mg, 8
mmol) under an Ar atmosphere, and the suspension was stirred at rt
until it turned lime green. Olefin 8 (2.7 mL, 30 mmol) was poured
into the green suspension, and then a solution of the corresponding
ozonide (4 or 6) (2 mmol) in THF (2 mL) was slowly added during
60 min. The mixture was stirred during 4 h, Et2O (20 mL) was added,
and the solution was washed with 2 N HCl and brine. The organic
layer was dried over anhydrous Na2SO4, and the solvent removed.
Flash chromatography (hexane/t-BuOMe mixtures) of the residue
gave products 12, 16, and 22 or 14, 17, and 24 in yields indicated in
Table 1(SC column).
Ozonide 4. Commercial 4-allyl-1-(benzyloxy)-2-methoxybenzene
(benzyl eugenol) was ozonized to 4 (78%): colorless oil; IR (film) νmax
1
1514, 1608, 1746, 1770, 2955 cm−1; H NMR (300 MHz, CDCl3) δ
7.48−7.30 (m, 5H), 6.88 (d, J = 8.5 Hz, 1H); 6.86 (d, J = 2.0 Hz, 1H),
6.78 (dd; J = 8.1, 2.0 Hz, 1H), 5.36 (t, J = 4.8 Hz, 1H), 5.18 (s, 1H),
5.17 (s, 2H), 5.09 (s, 1H), 3.92, (s, 3H), 3.0 (d, J = 4.9 Hz, 2H); 13C
NMR (75 MHz, CDCl3, DEPT) δ 149.6 (C), 147.3 (C), 137.2 (C),
128.5 (CH), 127.8 (CH), 127.6 (C), 127.3 (CH), 121.7 (CH), 114.0
(CH), 113.4 (CH), 103.6 (CH); 94.1 (CH2), 71.0 (CH2),55.9 (CH3),
31.6 (CH2); HRMS (EI) m/z calcd for C17H18O5 [M]+ 302.1154,
found 302.1166.
Ozonide 5. Commercial allylpentafluorobenzene was ozonized to 5
(65%): colorless oil; IR (film) νmax 1429, 1524, 2850, 2919, 2965
cm−1; 1H NMR (300 MHz, CDCl3) δ 5.48 (m, 1H), 5.14 (s, 1H), 5.07
(s, 1H), 3.12 (m, 2H); 13C NMR (75 MHz, CDCl3, DEPT) δ 101.5
(CH), 94.2 (CH2), 25.8 (CH2), (aromatic carbon signals could not be
observed, possibly due to the lack of NOE together with the splitting
derived from the coupling to fluorine atoms); HRMS (EI) m/z calcd
for C9H5F5O3 [M]+ 256.0159, found 256.0187.
1
Cross-Coupling product 16. Colorless oil: H NMR (500 MHz,
CDCl3) δ; 7.43 (d, J = 7.5 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.29 (d, J
= 7.5 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.73 (br s, 1H), 6.65 (d, J =
8.1 Hz, 1H), 5.12 (s, 2 H), 4.12 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 2.58
(t, J = 7.6 Hz, 2H), 2.31 (t, J = 7.4 Hz, 2H), 1.92 (quintuplet, 2H),
1.25 (t, J= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, DEPT) δ 173.5
(C), 149.6 (C), 146.5 (C), 137.4 (C), 134.8 (C), 128.4 (CH), 127.7
(CH), 127.2 (CH), 120.4 (CH), 114.4 (CH), 112.5 (CH), 71.3
(CH2), 60.2 (CH2), 56.0 (CH3), 34.7 (CH2), 33.6 (CH2), 26.6 (CH2),
14.2 (CH3); HRMS (EI): m/z calcd for C20H24O4Na [M + Na]+
351.1572, found 351.1582.
Cross-Coupling Product 17. Colorless oil: 1H NMR (500 MHz,
CDCl3) δ 7.42 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 4.11 (q, J
= 7.1 Hz, 2H), 3.81 (s, 3H), 2.30 (t, J = 7.4 Hz, 2H), 1.72−1.58 (m,
2H), 1.24 (t, J = 7.1 Hz, 3H), 0.84−0.62 (m, 2H), 0.25 (s, 6H); 13C
NMR (100 MHz, CDCl3, DEPT) δ 173.5 (C), 160.3 (C), 134.9
(CH), 129.8 (C), 113.5 (CH), 60.1 (CH2), 55.0 (CH3), 37.9 (CH2),
19.7 (CH2), 15.7 (CH2), 14.2 (CH3), −2.3 (CH3); HRMS (EI) m/z
calcd for C15H24O3NaSi [M + Na]+ 303.1392, found 303.1398.
General Procedure for Ti-Catalyzed Opening of Ozonides.
Deoxygenated THF (20 mL) was added to a mixture of Cp2TiCl2 (50
mg, 0.2 mmol) and Mn dust (439 mg, 8 mmol) under an Ar
atmosphere, and the suspension was stirred at rt until it turned lime
green (after about 15 min). A solution of 2,4,6-collidine (848 mg, 7
mmol) and Me3SiCl (434 mg, 4 mmol) in THF (2 mL) was poured
into the green suspension, and then the corresponding ozonide (1−7)
(1 mmol) in THF (2 mL) was added and the mixture stirred for 3 h.
Et2O (20 mL) was added and the solution washed with 2 N HCl and
Ozonide 6. Commercial allyl(4-methoxyphenyl)dimethylsilane was
ozonized to 6 (70% yield): colorless oil; IR (film) νmax 826, 1112,
1
1248, 1503, 1595, 2896, 2956 cm−1; H NMR (300 MHz, CDCl3) δ
7.57 (d, J = 8.5 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 5.28 (t, J = 6.1 Hz,
1H); 5.25 (s, 1H), 5.07 (s, 1H), 3.87 (s, 3H), 1.40 (d, J = 6.1 Hz, 2H),
0.48 (s, 3H), 0.47 (s, 3H); 13C NMR (75 MHz, CDCl3, DEPT) δ
160.7 (C), 135.0 (CH), 128.4 (C), 113.7 (CH), 103.1 (CH), 94.1
(CH2), 54.9 (CH3), 18.6 (CH2), −2.0 (CH3), −2.2 (CH3); HRMS
(EI) m/z calcd for C12H18O4Si [M]+ 254.0974, found 254.1003.
Ozonide 7. Commercial 7-bromo-1-heptene was ozonized to 7
(68% yield): colorless oil; IR (film) νmax 1059, 1111, 1453, 1461, 2889,
1
2936 cm−1; H NMR (300 MHz, CDCl3) δ 5.18 (s, 1H), 5.14 (t, J =
4.9 Hz, 1H), 5.03 (s, 1H), 3.40 (t, J = 6.7 Hz, 2H), 1.91−1.83 (m,
2H), 1.77−1.72 (m, 2H), 1.51−1.45 (m, 4H); 13C NMR (75 MHz,
CDCl3, DEPT) δ 103.5 (C), 94.0 (CH2), 33.4 (CH2), 32.4 (CH2),
30.9 (CH2), 27.8 (CH2), 22.9 (CH2); HRMS (EI) m/z calcd for
C7H14O3Br [M + H]+ 225.0126, found 225.0150.
General Procedure for Ti-Promoted Opening of Ozonides.
Deoxygenated THF (20 mL) was added to a mixture of Cp2TiCl2
(743 mg, 3 mmol) and Mn dust (439 mg, 8 mmol) under an Ar
atmosphere, and the suspension was stirred at rt until it turned lime
green (after about 15 min). A solution of the corresponding ozonide
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dx.doi.org/10.1021/jo300344a | J. Org. Chem. 2012, 77, 4171−4176