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(10 mL) at 0 °C. The reaction mixture was allowed to warm to room
temperature and stirred for 18 h. The reaction mixture was then diluted
with CH2Cl2 (100 mL) and washed with 1 N HCl aq (2 × 50 mL),
NaHCO3 aq (50 mL), and brine (50 mL). The organic layer was dried
(MgSO4), filtered, and the filtrate concentrated under reduced pressure,
and the residue was purified by flash chromatography on silica gel using a
mixture of ethyl acetate and hexanes (1:1) to give acrylamide 11 as a
light yellow oil, which solidified upon standing (2.21 g, 94%): 1H NMR
(300 MHz, CDCl3) δ 3.08 (dd, J = 7.0, 1.8 Hz, 2H, CH2CHNH), 3.69
(s, 3H, OCH3), 3.72 (m, 3H, OCH3), 5.30 (q, J = 7.3 Hz, 1H, CHNH),
5.57 (dd, J = 10.0, 1.6 Hz, 1H, CHHCHCO), 6.02−6.30 (m, 3H,
CHHCHCONH), 6.59−6.84 (m, 6H, 6 × CHAr), 7.10−7.26 (m, 2H,
2 × CHAr); 13C NMR (75.5 MHz, CDCl3) δ 42.37 (CH2CHNH), 54.33
(CH2CHNH), 55.00 (OCH3), 55.09 (OCH3), 112.24 (CHAr), 112.58
(CHAr), 112.61 (CHAr), 114.64 (CHAr), 118.85 (CHAr), 121.57 (CHAr),
126.54 (CH2CHCONH), 129.21 (CHAr), 129.49 (CHAr), 130.70
(CH2CHCONH), 138.70 (CAr), 142.97 (CAr), 159.43 (C−OMe),
159.60 (C−OMe), 164.78 (CO); HRMS (MALDI) 334.0360
(C19H21NNaO3 (M + Na+) requires 334.1414).
Friedel−Crafts Alkylation-Cyclization General Procedure.
Tetrachlorocyclopropene (0.19 mL, 1.90 mmol) was added to a
suspension of aluminum trichloride (910 mg, 6.88 mmol) in dry CH2Cl2
(15 mL). The resulting mixture was stirred for 10 min at room
temperature and then cooled to −20 °C. A cold (−20 °C) solution of
amide 10 (510 mg, 1.72 mmol) or acrylamide 11 (543 mg, 1.72 mmol)
in CH2Cl2 (10 mL) was then added dropwise. The reaction mixture was
stirred for 2 h at −20 °C, then warmed to room temperature and stirred
for one more hour. The reaction was then quenched by careful addition
of water (5 mL). The resulting mixture was vigorously stirred for 30 min,
and the organic phase was extracted with CH2Cl2 (3 × 20 mL) and ethyl
acetate (3 × 10 mL). The organic fractions were combined, dried
(MgSO4), filtered, and the filtrate concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel using a
gradient of 50−70% acetone in hexanes to give pure cyclopropenone 12
and 13, respectively.
(C−OMe), 164.28 (CO); HRMS (MALDI) 333.0661 (C21H19NO3
(M+ − CO) requires 333.1365).
General Procedure for the Deprotection of Phenols. A
solution of boron tribromide in CH2Cl2 (1.0 M, 2.86 mL, 2.86 mmol)
was added dropwise to a suspension of amide-cyclopropenone 12
(100 mg, 0.29 mmol), or acrylamide-cyclopropenone 13 (105 mg,
0.29 mmol) in CH2Cl2 (10 mL) at −78 °C. The reaction was allowed
to warm to room temperature and was stirred for 18 h. The reaction
was carefully quenched by slow addition of water (5 mL), and the
resulting mixture was extracted with CH2Cl2 (3 × 20 mL) and ethyl
acetate (3 × 20 mL). The combined organic fractions were dried
(MgSO4), filtered, and the filtrate concentrated in vacuo. The resulting
residue was purified by flash column chromatography on silica gel
using a gradient of 5−10% methanol in CH2Cl2 to give diphenol 18
and 19, respectively.
N-(4,9-Dihydroxy-1-oxo-6,7-dihydro-1H-dibenzo[a,e]-
cyclopropa[c]cycloocten-6-yl)acetamide 18. Orange solid (68 mg,
74%): IR (KBr) ν 3291 (s, br, OH), 1854 (s, CO cyclopropenone),
1642 (m), 1600 (s), 1569 (s), 1448 (m), 1357 (m), 1298 (m), 1264 (w),
1232 (w), 1209 (w), 1137 (w), 870 (w), 827 (w) cm−1; 1H NMR (300
MHz, d6-DMSO) δ 1.99 (s, 3H, CH3), 2.80 (d, J = 13.9 Hz, 1H,
CHHCHNH), 3.16−3.22 (m, 1H, CHHCHNH), 4.65 (brs, 1H,
CHNH), 6.82−6.91 (m, 4H, 4 × CHAr), 7.69−7.72 (m, 2H, 2 ×
CHAr), 8.92 (d, J = 7.8 Hz, 1H, NH); 13C NMR (75.5 MHz, d6-DMSO)
δ 22.65 (CH3), 44.25 (CH2CHNH), 55.29 (CH2CHNH), 111.70
(CHAr), 113.11 (CAr), 114.09 (CHAr), 114.43 (CHAr), 114.80 (CAr),
116.72 (CHAr), 134.97 (CHAr), 135.37 (CHAr), 140.89 (CC), 141.46
(CC), 146.17 (CAr), 149.28 (CAr), 151.73 (CO), 161.06 (C−OH),
161.30 (C−OH), 169.15 (CO); HRMS (MALDI) 316.0553
(C18H15NO3 (M + Na+ − CO) requires 316.0944).
N-(4,9-Dihydroxy-1-oxo-6,7-dihydro-1H-dibenzo[a,e]-
cyclopropa[c]cycloocten-6-yl)acrylamide 19. Orange solid (58
mg, 60%): IR (KBr) ν 3153 (s, br, OH), 1849 (s, CO cyclo-
propenone), 1661 (s), 1610 (m), 1447 (w), 1355 (w), 1302 (w), 1250
(w), 1133 (w), 980 (w), 874 (w), 826 (m), 754 (w), 665 (w) cm−1; 1H
NMR (300 MHz, d6-DMSO) δ 2.88 (d, J = 14.5, 1H, CHHCHNH),
3.14 (dd, J = 14.2, 3.8 Hz, 1H, CHHCHNH), 4.76 (brs, 1H, CHNH),
5.71 (dd, J = 10.2, 1.9 Hz, 1H, CHHCHCO), 6.11 (dd, J = 17.1, 1.9 Hz,
1H, CHHCHCO), 6.43 (dd, J = 17.1, 10.2 Hz, 1H, CH2CHCO), 6.80−
6.88 (m, 4H, 4 × CHAr), 7.68−7.77 (m, 2H, 2 × CHAr), 9.03 (d, J = 8.0
Hz, 1H, NH), 10.56 (brs, 2H, 2 × OH); 13C NMR (75.5 MHz, d6-
DMSO) δ 44.43 (CH2CHNH), 55.14 (CH2CHNH), 111.48 (CHAr),
113.03 (CAr), 114.13 (CHAr), 114.42 (CHAr), 114.69 (CAr), 116.61
(CHAr), 126.33 (CH2CHCONH), 131.10 (CH2CHCONH), 134.93
(CHAr), 135.39 (CHAr), 140.82 (CC), 141.45 (CC), 145.86 (CAr),
148.76 (CAr), 151.51 (CO), 161.09 (C−OH), 161.26 (C−OH),
N-(4,9-Dimethoxy-1-oxo-6,7-dihydro-1H-dibenzo[a,e]-
cyclopropa[c]cycloocten-6-yl)acetamide 12. White solid (290
mg, 48%): IR (KBr) ν 3304 (s, NH), 3062 (w), 2941 (w), 2837 (w),
1846 (s, CO cyclopropenone), 1644 (m), 1609 (s), 1562 (m), 1431
(m), 1348 (m), 1251 (m), 1137 (w), 1024 (w), 826 (w) cm−1; 1H NMR
(300 MHz, d6-DMSO) δ 1.99 (s, 3H, CH3), 2.88 (dd, J = 14.5, 1.5 Hz,
1H, CHHCHNH), 3.17 (dd, J = 14.8, 4.6 Hz, 1H, CHHCHNH), 3.87
(s, 6H, 2 × CH3O), 4.73 (brs, 1H, CHNH), 7.02−7.08 (m, 4H, 4 ×
CHAr), 7.84−7.87 (m, 2H, 2 × CHAr), 8.79 (d, J = 8.1 Hz, 1H, NH); 13
C
NMR (75.5 MHz, d6-DMSO) δ 22.60 (CH3), 44.51 (CH2CHNH),
54.86 (CH2CHNH), 55.67 (2 × CH3O), 111.13 (CHAr), 111.72
(CHAr), 112.55 (CHAr), 114.52 (CAr), 115.73 (CHAr), 116.09 (CAr),
134.97 (CHAr), 135.41 (CHAr), 141.69 (CC), 142.47 (CC), 145.88
(CAr), 148.83 (CAr), 151.58 (CO), 162.13 (C−OMe), 162.41
(C−OMe), 169.01 (CO); HRMS (MALDI) 321.0652 (C20H19NO3
(M+ − CO) requires 321.1365).
164.21 (CO); HRMS (MALDI) 306.0514 (C19H16NO3 (MH+
−
CO) requires 306.1130).
Sulfation General Procedure. Sulfur trioxide pyridine complex
(290 mg, 1.870 mmol) was added to a solution of amide-cyclopropenone
18 (30 mg, 0.093 mmol) or acrylamide-cyclopropenone 19 (31 mg,
0.093 mmol) in DMF (5 mL), and the resulting mixture was stirred for
2 h. The reaction was quenched by addition of pyridine in methanol
(5 mL, 1:1 v:v). The solvent was then evaporated under reduced
pressure at room temperature (please note that the pyridinium salt of
sulfated product is unstable). The residue was then purified by C-18
column chromatography using a gradient of 0−15% CH3CN in H2O to
give a pyridinium salt of 14 and 15, respectively, which was then passed
through a Na+ ion-exchange resin (see for resin details the Supporting
Information) and lyophilized to give compounds 14 and 15, respectively.
N-(4,9-Sodium Disulfate-1-oxo-6,7-dihydro-1H-dibenzo-
[a,e]cyclopropa[c]cycloocten-6-yl)acetamide 14. White powder
(28 mg, 57%): IR (KBr) ν 3456 (s, br), 1854 (s, CO
cyclopropenone), 1607 (s), 1565 (m), 1420 (w), 1360 (m), 1245
(s), 1051 (s), 957 (m), 894 (w), 786 (m) cm−1; 1H NMR (300 MHz,
D2O) δ 2.17 (s, 3H, CH3), 2.95 (d, J = 13.6 Hz, 1H, CHHCHNH),
3.27 (dd, J = 15.4, 4.5 Hz, 1H, CHHCHNH), 4.87 (brs, 1H, CHNH),
7.42−7.45 (m, 4H, 4 × CHAr), 8.04−8.08 (m, 2H, 2 × CHAr); 13C
NMR (75.5 MHz, D2O) δ 21.95 (CH3), 44.13 (CH2CHNH), 55.73
(CH2CHNH), 116.94 (CHAr), 118.30 (CAr), 119.95 (CAr), 120.34
N-(4,9-Dimethoxy-1-oxo-6,7-dihydro-1H-dibenzo[a,e]-
cyclopropa[c]cycloocten-6-yl)acrylamide 13. White solid (344
mg, 55%): IR (KBr) ν 3280 (m, NH), 3080 (w), 2927 (m), 2851 (w),
1848 (s, CO cyclopropenone), 1728 (w), 1658 (m), 1608 (s), 1561
(m), 1500 (w), 1429 (w), 1407 (w), 1350 (m), 1309 (m), 1289 (m),
1252 (s), 1135 (m), 1074 (w), 1054 (w), 1020 (w), 957 (w), 837 (w),
832 (w) cm−1; 1H NMR (300 MHz, d6-DMSO) δ 2.94 (dd, J = 14.6, 1.2
Hz, 1H, CHHCHNH), 3.23 (dd, J = 14.8, 4.5 Hz, 1H, CHHCHNH),
3.85 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 4.85 (brs, 1H, CHNH), 5.71
(dd, J = 10.2, 1.8 Hz, 1H, CHHCHCO), 6.11 (dd, J = 17.1, 1.8 Hz, 1H,
CHHCHCO), 6.44 (dd, J = 17.1, 10.2 Hz, 1H, CH2CHCO), 6.97−7.09
(m, 4H, 4 × CHAr), 7.85−7.89 (m, 2H, 2 × CHAr), 9.05 (d, J = 8.2 Hz,
1H, NH); 13C NMR (75.5 MHz, d6-DMSO) δ 44.46 (CH2CHNH),
54.89 (CH2CHNH), 55.65 (OCH3), 55.67 (OCH3), 111.14 (CHAr),
111.71 (CHAr), 112.62 (CHAr), 114.53 (CAr), 115.71 (CHAr), 116.08
(CAr), 126.36 (CH2CHCONH), 131.08 (CH2CHCONH), 135.01
(CHAr), 135.50 (CHAr), 141.63 (CC), 142.53 (CC), 145.73
(CAr), 148.39 (CAr), 151.56 (CO), 162.16 (C−OMe), 162.39
5386
dx.doi.org/10.1021/ja3002666 | J. Am. Chem. Soc. 2012, 134, 5381−5389