A R T I C L E S
Zhong et al.
1
7.42 (d, 1H), 7.24 (d, 1H), 6.97 (dd, 1H), 2.57 (q, 2H), 1.24 (t, 3H);
13C NMR (75 MHz, CDC13) δ 172.2, 149.3, 132.7, 130.5, 129.4, 123.8,
121.2, 27.5, 8.80; HRMS (CI+) calcd for C9H 9 O2Cl2 218.9980, found
218.9970.
solid. H NMR (300 MHz CDCl3) δ 11.7 (s, 1H), 7.52 (s, 1H), 7.33
(dd, 1H), 6.93 (d,1H), 5.76 (dq, 1H), 2.31 (s, 3H), 1.69 (dd,3H); 13C
NMR (75 MHz, CDC13) δ 201.3, 201.0, 161.2, 138.3, 129.3, 128.3,
118.5, 116.3, 89.8, 87.4, 20.5, 18.7, 18.4; HRMS (CI+) calcd for
C10H13O2 165.0916, found 165.0915.
General Procedure for Preparation of 1-(2-Hydroxyphenyl)-
propan-1-ones via the Fries Rearrangement. To the phenylpro-
panoates (near 14 mmol) in a flame-dried one-neck flask fitted with a
condenser and heated to 110 °C was quickly added solid AlCl3 (near
15 mmol). The resulting dark material was heated for 90 min, cooled
to rt, and taken up in 4 N HCl (50 mL). The aqueous phase was
extracted with ether (2 × 50 mL), and ethyl acetate (3 × 50 mL), and
then the combined organics were washed with 1 N sodium acetate (50
mL) and brine (50 mL). After drying with Na2SO4, vacuum filtration,
and concentration by rotary evaporation at 40 °C, the crude material
was purified by flash chromatography (96/4 hexanes/EtOAc), leaving
the product as a white solid (yields typically in the range of 90-95%).
1-(2-Hydroxy-5-methylphenyl)propan-1-one (4a). The red amor-
phous solid was purified by flash chromatography (97:3 hexanes/
EtOAc) leaving 4a as a yellow liquid. 1H NMR (300 MHz, CDC13) δ
12.2 (s, 1H), 7.53 (d, 1H), 7.28 (dd, 1H), 6.87 (d, 1H), 3.01 (q, 2H),
2.30 (s, 3H), 1.23 (t, 3H); HRMS (CI+) calcd for C10H 13 O2 165.0916,
found 165.0921.
2-Fluoro-1-(2-hydroxy-5-nitrophenyl)propan-1-one (2c). To a -78
°C solution of 1.0 M sodium bis(trimethylsilyl)amide (14.0 mL, 14.0
mmol) in a three-neck flask fitted with an addition funnel was added
1-(2-hydroxy-5-nitrophenyl)propan-1-one (4c) (0.870 g, 4.46 mmol)
dissolved in THF (9.0 mL) dropwise. The solution stirred for 90 min.
at -78 °C under argon, and then chlorotrimethylsilane (2.0 mL, 15.7
mmol) dissolved in THF (2.0 mL) was added dropwise. The resulting
solution was mixed for 1 h at -78 °C and then allowed to warm to rt
for 1 h. Solid tert-butyl alcohol (1.2 g, 16 mmol) was quickly added to
quench excess base, and the solution was transferred via cannula to
Selectfluor (1.95 g, 5.50 mmol) dissolved in acetonitrile (50 mL) and
trifluoroacetic acid (0.150 mL). (Note: Selectfluor is difficult to dissolve
at rt even with prolonged sonication. The addition of trifluoroacetic
acid assists in dissolving the reagent.) The combined solutions were
mixed for 1 h at rt, and then tetrabutylammonium fluoride trihydrate
(5.63 g, 17.8 mmol) was added, turning the solution bright yellow.
After 30 min, H2O was added (100 mL) and the solution stirred for 14
h. The layers were separated, and the aqueous phase was acidified with
concentrated HCl (5 mL) and extracted with EtOAc (3 × 50 mL). The
combined organics were washed with brine (75 mL), dried over Na2-
SO4, vacuum filtered, and concentrated by rotary evaporation at 40
°C. The heavy orange liquid was purified by flash chromatography
(elution gradient from 9:1 hexanes/EtOAc to 1:1 hexanes/EtOAc,
followed by a purge with 98:2 EtOAc/AcOH), providing 0.665 g (70%)
of 2c as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 12.3 (s,
1H), 8.79 (d, 1H), 8.32 (dd, 1H), 7.09 (d, 1H), 5.78 (dq, 1H), 1.71 (dd,
3H); 13C NMR (75 MHz, CDCl3) δ 201.4, 201.1, 167.6, 139.6, 131.4,
126.8, 119.7, 115.5, 90.7, 88.3, 18.1, 17.8; HRMS (CI+) calcd for C9H9-
NO4F 214.0516, found 214.0516.
1-(4,5-Dichloro-2-hydroxyphenyl)propan-1-one (4b). Reactants
were heated at 160 °C for 3 h before cooling to rt. The white solid
obtained after workup was purified by flash chromatography (95:5
hexanes/EtOAc), when necessary, leaving 4b as a white solid: 1H NMR
(300 MHz, CDC13) δ 12.2 (s, 1H), 7.80 (s, 1H), 7.09 (s, 1H), 2.99 (q,
2H), 1.23 (t, 3H); 13C NMR (75 MHz, CDC13) δ 205.5, 160.9, 139.9,-
130.5, 122.3, 120.3, 118.6, 31.7, 7.83; HRMS (CI+) calcd for C9H
9
O2Cl2 218.9980, found 218.9976.
1-(2-Hydroxy-5-nitrophenyl)propan-1-one (4c). To a rapidly stirred
-78 °C solution of 1-(2-methoxy-5-nitrophenyl)propan-1-one (5) (1.34
g, 6.38 mmol) in dry dichloromethane (20 mL) was added 1 M BCl3
in dichloromethane (18 mL, 18 mmol). After being gradually warmed
to room temperature over 14 h, the solution was poured onto 1 N sodium
acetate (30 mL) and shaken well. The organic phase was separated,
and the aqueous phase was extracted with dichloromethane (25 mL).
The combined organics were washed with brine (30 mL), dried over
sodium sulfate, vacuum filtered, and concentrated by rotary evaporation
at 35 °C. The crude solid was purified using flash chromatography
(short column; 9:1 hexanes/EtOAc) leaving 4c as a white solid in 92%
yield. 1H NMR (300 MHz, CDC13) δ 13.0 (s, 1H), 8.75 (d, 1H), 8.34
(dd, 1H), 7.09 (d, 1H) 3.16 (q, 2H), 1.29 (t, 3H); 13C NMR (75 MHz,
CDC13) δ 206.5, 167.1, 139.5, 130.8, 126.3, 119.6, 118.0, 31.8, 7.78;
HRMS (CI+) calcd for C9H9NO3: 196.0610, found 196.0607.
1-(4,5-Dichloro-2-hydroxyphenyl)-2-fluoropropan-1-one (2b). To
a -78 °C solution of 1-(4,5-dichloro-2-hydroxyphenyl)propan-1-one
(1.45 g, 6.62 mmol) and THF (7.0 mL) in a three-neck flask fitted
with an addition funnel was added 1.0 M sodium bis(trimethylsilyl)-
amide (13.4 mL, 13.4 mmol) rapidly in one portion. The solution was
stirred for 90 min at -78 °C under argon, and then N-fluorobenzene
sulfonamide (2.30 g, 7.29 mmol) dissolved in THF (8.0 mL) was added
slowly dropwise. The solution was mixed for 90 min at -78 °C and
then was allowed to warm to rt (45-60 min.). Ammonium chloride (1
N, 30 mL) was added, and the aqueous phase was extracted with EtOAc
(2 × 25 mL). The combined organics were washed with brine (30 mL),
dried over Na2SO4, vacuum filtered, and concentrated by rotary
evaporation at 40 °C. The crude oil was purified by flash chromatog-
raphy (97.3 hexanes/EtOAc), providing 1.08 g (69%) of 2b as a yellow
solid: 1H NMR (300 MHz CDCl3) δ 11.8 (s, 1H), 7.94 (s, 1H), 7.14
(s, 1H), 5.62 (dq, 1H), 1.70 (dd, 3H); 13C NMR (75 MHz, CDCl3) δ
200.4, 200.1, 161.9, 141.3, 130.9, 122.8, 120.5, 116.1, 90.9, 88.5, 18.3,
18.0; HRMS (CI+) calcd for C9H8O2 FCl2: 236.9885, found 236.9883.
2-Fluoro-1-(2-hydroxy-5-methylphenyl)propan-1-one (2a). The
same procedure as above was followed. The crude oil was purified by
flash chromatography (96:4 hexanes/EtOAc) affording 2a as a beige
Method of pKa Determination in Acetonitrile. The pKa values of
the phenolic hydroxy groups of 1 in acetonitrile were determined by
measuring relative acidities using a UV-vis spectrophotometric titration
technique.31 At first, the acid to be measured (HA) and a reference
acid (HR) with known pKa were titrated separately to obtain the spectra
of the neutral (HA and HR) and deprotonated (A- and R-) forms of
both acids at known concentrations. Then, a solution containing the
two acids was titrated with a transparent base. During the titration, 10
to 20 spectra at different acidities after each addition of a small amount
of the base were recorded, including those where both acids were in
neutral or fully deprotonated form. The spectra of the mixed acid
solution titration were resolved to the individual spectra of HA, A-,
HR, and I- by multiple linear regression by using Origin (Microcal
Software, Inc.). Thus, the value of [HA][R-]/[A-][HR] was obtained.
Since both acids were in the same solution, the value of activity ratio
-
-
aHAaI /aA aHR should be almost the same as the concentration ratio
[HA][R-]/[A-][HR]. The pKa of HA was readily calculated with the
equation of pKa (HA) ) pKa (HR) + log([HA][R-]/[A-][HR]). From each
titration experiment, the pKa was determined as the mean of 5 to 10
values from the spectra where both [HA]/[A-] and [R-]/[HR] were
not extremely large or small (values between 0.2 and 0.8 were
preferred). To measure the concentration correctly, the difference
between the two acids’ pKas should be less than two units, and the two
acids and their deprotonated forms should have apparent differences
in their absorbance spectra; otherwise, the mixed spectra could not be
resolved properly. By this technique, it is not necessary to know the
accurate concentrations of the acids. Further, the results were not
(30) Powell, M. T.; Porte, A. M.; Reibenspies, J.; Burgess, K. Tetrahedron 2001,
57, 5027-5038.
(31) Leito, I.; Kaljurand, I.; Koppel, I. A.; Yagupolskii, L. M.; Vlasov, V. M.
J. Org. Chem. 1998, 63, 7868. Leito, I.; Rodima, T.; Koppel, I. A.;
Schwesinger, R.; Vlasov, V. M. J. Org. Chem. 1997, 62, 8479.
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3494 J. AM. CHEM. SOC. VOL. 126, NO. 11, 2004