Green organocatalytic α-hydroxylation of ketones

Article abstract of DOI:10.1039/c6ob00036c

An efficient and green method for the α-hydroxylation of substituted ketones has been developed. This method includes the in situ conversion of various ketones into the corresponding silyl enol ethers and their oxidation to the corresponding α-hydroxy ketones. Two protocols have been established leading either to protected α-hydroxy carbonyls or free α-hydroxy ketones. Both procedures are easy to follow and lead to good to high yields for a variety of ketones.

Full text of DOI:10.1039/c6ob00036c

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Biomolecular Chemistry
DOI: 10.1039/C6OB00036C
PAPER
Green organocatalytic α-hydroxylation of ketones
Errika Voutyritsa, Alexis Theodorou and Christoforos G. Kokotos*
Received 00th January 20xx,
Accepted 00th January 20xx
An efficient and green method for the α-hydroxylation of substituded ketones has been developed. This method includes
the in situ conversion of variοus ketones into the corresponding silyl enol ethers and their oxidation to the corresponding
α-hydroxy ketones. Two protocols have been established leading either to protected α-hydroxy carbonyls or free α-
hydroxy ketones. Both procedures are easy to follow and lead to good to high yields for a variety of ketones.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
methods for the preparation of α-hydroxy ketones involve iodine
reagents11 and metal-based procedures utilizing Pd,12a Sn12b and
Ru.12c,d Finally, a number of α-hydroxylation procedures of carbonyl
compounds have been developed in organocatalysis.13
The α-hydroxy ketone subunit is an important motif found in a
diverse range of biologically relevant molecules and constitutes a
valuable synthetic target. It is also a flexible intermediate in the
synthesis of many pharmaceuticals,1,2 as well as for the synthesis of
depsipeptides and natural products of biological importance.3 The
construction of the C-O bond is crucial not only because its
biological functions, but also because this architecture is useful for
directing further stereoselective elaboration. The classical method
for the preparation of α-hydroxy carbonyl compounds involves
substitution of α-amino or α-halo carbonyls with hydroxides. In
literature, the synthesis of α-hydroxy ketones can also be
performed by the reduction of diketones4 or via enolisation of α-
methylene carbonyl compounds and reaction with an electrophilic
oxygen source like organic peracids,5 singlet oxygen,6 osmium
tetroxide,7 and ozonolysis.8 Among several synthetic protocols, the
Rubbotom oxidation, which involves the epoxidation of silyl enol
ethers to generate silyl-protected α-hydroxy ketones, has been one
of the most widely used methods.5a,9 α-Hydroxy ketones can also
prepared by the oxidation of epoxides and aziridines.10 Direct
In recent years, our interest lies on developing novel
organocatalytic methodologies that can lead to useful organic
intermediates. Along these lines, we have developed an
organocatalytic α-amination of branched aldehydes.14 More
recently, we turned our attention on the organocatalytic activation
of hydrogen peroxide. Since hydrogen peroxide by itself is a poor
oxidant for organic oxidations, it has to be coupled with a catalyst
or a reagent to create a reactive intermediate that will carry out the
oxidation. A couple of years ago, we have introduced 2,2,2-
trifluoroacetophenone, among a number of activated ketones, as
an efficient organocatalyst for the oxidation of silanes to silanols,15a
tertiary amines and azines to N-Oxides15b and alkenes to
epoxides.15c Also, the same protocol was extended in the oxidation
of N-allyl tertiary amines, followed by
a
Meisenheimer
rearrangement leading to O-allyl hydroxyl amines.15d In general, this
oxidation protocol is environmentally friendly, as the only
byproduct is water.
Herein, our design plan involves the successful employment of
this organocatalytic oxidative protocol on enol ethers to afford α-
hydroxy ketones. Our final target would be the synthesis of the silyl
enol ethers from the corresponding ketone and the in situ oxidation
of the enolate to the corresponding α-hydroxy ketones.
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodestrian
University of Athens, Panepistimiopolis, Athens 15771, Greece. E-mail:
ckokotos@chem.uoa.gr
Electronic Supplementary Information (ESI) available: [1H and 13C NMR data]. See
DOI: 10.1039/x0xx00000x
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successfully leading to good to high DyOieIl:d1s0.1(033b9V-/iedCw)6.AOrtBHic0lae0lO0on3gl6einCne
substituents were also well tolerated either at para- or ortho-
position, leaving room for further synthetic manipulations on the
aromatic ring (3e-h). Substrates bearing free hydroxyl groups on the
aromatic ring can also be employed leading to a double protection
(3i). Electron rich aromatic rings and heterocyclic aromatic methyl
ketones led also to good to high yields (3j-m). Substrates with larger
stereochemical hindrance led to slightly lower yields, but even
tertiary alcohol are possible to be formed by this method (3n, 3o).
In these cases, the corresponding products were obtained after
silica treatment, as the corresponding epoxides were more stable.
In an attempt to further extend this protocol, our focus turned
on one-pot deprotection of the silyl-group (Scheme 2). This was
found to be possible just by addition of p-toluenesulfonic acid in the
reaction mixture for 1 h. Starting from acetophenone, the α-
hydroxy ketone 4a was isolated in 76% yield. Alkyl-substituted
Results and discussion
Our initial concern whether the TBDMS-enol ether of acetophenone
could be oxidized under our previously-developed oxidative
reaction conditions were readily answered by preparing the silyl
enol ether and subjecting it in the oxidative reaction conditions,
leading to a quantitative conversion of TBDMS-protected alcohol
3a. We then turned our attention in developing an in situ protocol.
Indeed, it is possible to perform both the silyl enol ether formation
and the Rubottom-type oxidation in a single operation leading to
70% yield of protected alcohol 3a (Scheme 1). Filtration through a
Florisil plug and evaporation of THF before the oxidation was
proven to be necessary in order to maintain the yield of the
reaction. Among a variety of protecting groups that were tested
(TES, TMS, TIPS etc), TBDMS led to the best isolated yields of
products. Finally, the optimum reaction conditions were studied
and identified. A variety of substituted ketones were then tested,
leading to a number of TBDMS-protected α-hydroxy ketones
(Scheme 1). Alkyl-substituted aryl methyl ketones were used
Scheme 2 Organocatalytic synthesis of α-hydroxy ketones
Scheme 1 Organocatalytic synthesis of TBDMS-protected α-hydroxy ketones
2 | J. Name., 2012, 00, 1-3
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aromatic methyl ketones were also employed succefully (4b-d). are reported as follows: chemical shiftDO(δI: 10p.p10m3)9,/Ci6nOteBg0r0a0ti3o6nC,
Halogen-containing aromatics led to slightly lower yields, while multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
ortho-substituted aromatics were well tolerated (4e-h). It has to be multiplet, b s = broad signal, b s m = broad signal multiplet),
noted that selective deprotection of the alcohol in the presence of coupling constant and assignment. Data for 13C and 19F NMR are
the phenol was also possible (4i). In this case, electron rich aromatic reported in terms of chemical shift (δ ppm). Mass spectra and
methyl ketones afforded the highest yields (4j, 4k), while ketones conversions of the reactions were recorded on a Shimadzu GCMS-
bearing heterocyclic aromatic moieties led also to the desired QP2010 Plus Gas Chromatograph Mass Spectrometer utilizing a
product in good yield (4l, 4m). Substrates with further substitution MEGA column (MEGA-5, F.T: 0.25μm, I.D.: 0.25mm, L: 30m, Tmax:
on the alkyl side chain led again to slightly worse yields (4n, 4o). 350 oC, Column ID 11475).
Again, it has to be highlighted that tertiary alcohols were
Representative procedure for 3a-3b, 3e, 3g-3i
successfully generated with this protocol.
Substituted
acetophenone
(1.00
mmol)
and
tert-
butylchlorodimethylsilane (196 mg, 1.30 mmol) were placed in an
oven-dried round bottom flask sealed with a septum, under Ar
atmosphere, and dissolved in dry THF (4.0 mL). The solution was
cooled down to -78 oC and NaH (60% in oil, 160 mg, 4.00 mmol) was
added. The reaction mixture was stirred for 2 hours at room
temperature, filtered using florisil and the solvent removed under
vacuum. tBuOH (0.5 mL), 2,2,2-trifluoro-1-phenylethanone (17.4
Conclusions
In conclusion, a highly versatile and green protocol was developed
for the conversion of ketones into protected α-hydroxy ketones
using H2O2 as the oxidant. This method was further extended in the
synthesis of free α-hydroxy ketones. This method provides an
effective entry for the installation of α-hydroxy moieties into
ketones, a non-trivial task as appeared in literature. A variety of
substituted aromatic ketones, heteroaromatic ketones were
employed successfully leading to high to excellent yields in both
cases. When the alkyl chain was changed from methyl to higher
members of alkyl substituents, the protocol led to lower yields, but
it was still successful. Thus, these protocols can be extended in the
synthesis of both secondary and tertiary α-hydroxy ketones.
mg, 0.10 mmol), aqueous buffer solution (0.5 mL, 0.6M K2CO3
-
4x10-5M EDTA tetrasodium salt), acetonitrile (0.15 mL, 3.00 mmol)
and 30% aqueous H2O2 (0.36 mL, 3.00 mmol) were added
consecutively. After the addition, stirring was continued for another
1 hour at room temperature. The crude product was purified using
flash column chromatography (Pet. Ether) to afford the desired
product.
Experimental
Representative procedure for 3c-3d, 3f, 3j-3o
General methods
Substituted ketone (1.00 mmol) and tert-butylchlorodimethylsilane
(196 mg, 1.30 mmol) were placed in an oven-dried round bottom
flask sealed with a septum, under Ar atmosphere, and dissolved in
Chromatographic purification of products was accomplished using
forced-flow chromatography on Merck Kieselgel 60 F254 230-400
mesh. Thin-layer chromatography (TLC) was performed on
aluminum backed silica plates (0.2 mm, 60 F254). Visualization of
the developed chromatogram was performed by fluorescence
quenching using phosphomolybdic acid, anisaldehyde or potassium
permanganate stains. Melting points were determined on a Buchi
530 hot stage apparatus and are uncorrected. Mass spectra (ESI)
were recorded on a Finningan Surveyor MSQ LC-MS spectrometer.
HRMS spectra were recorded on Bruker Maxis Impact QTOF
spectrometer. 1H, 13C and 19F NMR spectra were recorded on Varian
Mercury (200 MHz, 50 MHz and 188 MHz respectively), and are
internally referenced to residual solvent signals. Data for 1H NMR
o
dry THF (4.0 mL). The solution was cooled down to -78 C and NaH
(60% in oil, 160 mg, 4.00 mmol) was added. The reaction mixture
was stirred for 30 minutes at room temperature, heated under
reflux for 2 hours at 85 oC, filtered using florisil and the solvent
removed under vacuum. tBuOH (0.5 mL), 2,2,2-trifluoro-1-
phenylethanone (17.4 mg, 0.10 mmol), aqueous buffer solution (0.5
mL, 0.6M K2CO3 - 4x10-5M EDTA tetrasodium salt), acetonitrile (0.15
mL, 3.00 mmol) and 30% aqueous H2O2 (0.36 mL, 3.00 mmol) were
added consecutively. After the addition, stirring was continued for
another 1 hour at room temperature. The crude product was
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purified using flash column chromatography (Pet. Ether) to afford d, J = 8.4 Hz, ArH), 4.90 (2H, s, OCH2), 0.92 (9H, s, 3 x CH3), 0.11 (6H,
DOI: 10.1039/C6OB00036C
the desired product.
s, 2 x CH3); 13C NMR (CDCl3) δ: 196.8, 137.5, 134.5 (q, J = 32.8 Hz),
128.4, 125.6 (q, J = 3.6 Hz), 123.5 (q, J = 272.7 Hz), 67.7, 25.7, 18.4, -
5.4; 19F NMR (CDCl3) δ: 16.2; MS (ESI) 319 (M+H+, 61%).
2-((tert-Butyldimethylsilyl)oxy)-1-phenylethanone (3a).16 Colorless
1
oil. 70% yield; H NMR (CDCl3) δ: 7.90 (2H, dt, J = 6.9 and 1.8 Hz,
ArH), 7.58-7.35 (3H, m, ArH), 4.91 (2H, s, OCH2), 0.92 (9H, s, 3 x
CH3), 0.11 (6H, s, 2 x CH3); 13C NMR (CDCl3) δ: 197.2, 134.7, 133.2,
128.5, 127.7, 67.3, 25.7, 18.4, -5.4; MS (ESI) 251 (M+H+, 67%).
1-(4-Bromophenyl)-2-((tert-butyldimethylsilyl)oxy)ethanone
(3g).18 White viscous oil. 62% yield; 1H NMR (CDCl3) δ: 7.81 (2H, d, J
= 8.4 Hz, ArH), 7.59 (2H, d, J = 8.4 Hz, ArH), 4.85 (2H, s, OCH2), 0.91
(9H, s, 3 x CH3), 0.11 (6H, s, 2 x CH3); 13C NMR (CDCl3) δ: 196.7,
133.5, 131.9, 129.6, 128.1, 67.3, 25.7, 18.4, -5.4; MS (ESI) 330
(M+H+, 55%).
2-((tert-Butyldimethylsilyl)oxy)-1-(p-tolyl)ethanone (3b). White
solid. Mp 39-41 oC; 74% yield; 1H NMR (CDCl3) δ: 7.81 (2H, d, J = 8.1
Hz, ArH), 7.22 (2H, d, J = 8.1 Hz, ArH), 4.86 (2H, s, OCH2), 2.37 (3H, s,
CH3), 0.92 (9H, s, 3 x CH3), 0.11 (6H, s, 2 x CH3); 13C NMR (CDCl3) δ:
196.9, 144.0, 132.2, 129.2, 127.9, 67.3, 25.7, 21.6, 18.4, -5.4; HRMS
calcd for C15H24NaO2Si [M+Na]+ 287.1438; found: 287.1443.
1-(2-Bromophenyl)-2-((tert-butyldimethylsilyl)oxy)ethanone (3h).
Yellow oil. 62% yield; 1H NMR (CDCl3) δ: 7.60-7.51 (1H, m, ArH),
7.44-7.35 (1H, m, ArH), 7.33-7.28 (2H, m, ArH), 4.69 (2H, s, OCH2),
0.85 (9H, s, 3 x CH3), 0.09 (6H, s, 2 x CH3); 13C NMR (CDCl3) δ: 202.4,
139.3, 133.2, 131.5, 128.5, 127.1, 118.7, 68.8, 25.6, 18.2, -5.5;
HRMS calcd for C14H21BrNaO2Si [M+Na]+ 351.0386; found:
351.0390.
1-([1,1'-Biphenyl]-4-yl)-2-((tert-butyldimethylsilyl)oxy)ethanone
o
1
(3c). White solid. Mp 89-91 C; 64% yield; H NMR (CDCl3) δ: 8.01
(2H, d, J = 8.3 Hz, ArH), 7.75-7.56 (4H, m, ArH), 7.51-7.37 (3H, m,
ArH), 4.96 (2H, s, OCH2), 0.95 (9H, s, 3 x CH3), 0.15 (6H, s, 2 x CH3);
13C NMR (CDCl3) δ: 197.0, 145.9, 139.8, 133.5, 128.9, 128.4, 128.2,
127.2, 127.2, 67.5, 25.8, 18.5, -5.3; HRMS calcd for C20H26NaO2Si
[M+Na]+ 349.1594; found: 349.1603.
2-((tert-Butyldimethylsilyl)oxy)-1-(2-((tert-
butyldimethylsilyl)oxy)phenyl)ethanone (3i). Yellow oil. 51% yield;
1
2.6 equiv. TBDMSCl were added; H NMR (CDCl3) δ: 7.81-7.66 (1H,
m, ArH), 7.41-7.29 (1H, m, ArH), 7.07-6.80 (2H, m, ArH), 4.84 (2H, s,
OCH2), 1.00 (9H, s, 3 x CH3), 0.92 (9H, s, 3 x CH3), 0.31 (6H, s, 2 x
CH3) 0.11 (6H, s, 2 x CH3); 13C NMR (CDCl3) δ: 199.9, 154.9, 133.1,
130.5, 128.3, 121.2, 119.6, 70.7, 29.7, 25.8, 22.7, 18.6, -3.8, -5.3;
HRMS calcd for C20H36NaO3Si [M+Na]+ 403.2095; found: 403.2101.
2-((tert-Butyldimethylsilyl)oxy)-1-(naphthalen-2-yl)ethanone
1
(3d).17 Colorless oil. 73% yield; H NMR (CDCl3) δ: 8.47 (1H, s, ArH),
8.12-7.79 (4H, m, ArH), 7.70-7.47 (2H, m, ArH), 5.05 (2H, s, OCH2),
0.96 (9H, s, 3 x CH3), 0.16 (6H, s, 2 x CH3); 13C NMR (CDCl3) δ: 197.4,
135.6, 132.3, 132.0, 129.5, 129.4, 128.4, 127.7, 126.8, 123.6, 67.6,
25.8, 18.5, -5.3 ; MS (ESI) 301 (M+H+, 82%).
2-((tert-Butyldimethylsilyl)oxy)-1-(4-methoxyphenyl)ethanone
(3j).19 Colorless oil. 89% yield; 1H NMR (CDCl3) δ: 7.90 (2H, d, J = 9.0
Hz, ArH), 6.90 (2H, d, J = 9.0 Hz, ArH), 4.85 (2H, s, OCH2), 3.83 (3H, s,
OCH3), 0.91 (9H, s, 3 x CH3), 0.10 (6H, s, 2 x CH3); 13C NMR (CDCl3) δ:
195.9, 163.4, 130.1, 127.7, 113.6, 67.2, 55.3, 25.7, 18.4, -5.4; MS
(ESI) 281 (M+H+, 72%).
2-((tert-Butyldimethylsilyl)oxy)-1-(4-fluorophenyl)ethanone (3e).17
o
1
White solid. Mp 37-39 C; 66% yield; H NMR (CDCl3) δ: 8.09-7.91
(2H, m, ArH), 7.19-7.05 (2H, m, ArH), 4.86 (2H, s, OCH2), 0.92 (9H, s,
3 x CH3), 0.11 (6H, s, 2 x CH3); 13C NMR (CDCl3) δ: 196.2, 166.2 (d, JCF
= 255.2 Hz), 132.8 (d, JCF = 9.6 Hz), 130.6 (d, JCF = 3.9 Hz), 115.7 (d,
JCF = 22.1 Hz), 67.4, 25.6, 18.4, -5.4; 19F NMR (CDCl3) δ: -24.7; MS
(ESI) 269 (M+H+, 75%).
2-((tert-Butyldimethylsilyl)oxy)-1-(2,4-dimethoxyphenyl)ethanone
(3k). Yellow viscous oil. 52% yield; 1H NMR (CDCl3) δ: 7.93 (1H, d, J =
8.7 Hz, ArH), 6.54 (1H, dd, J = 8.7 and 1.9 Hz, ArH), 6.43 (1H, d, J =
1.9 Hz, ArH), 4.81 (2H, s, OCH2), 3.87 (3H, s, OCH3), 3.84 (3H, s,
OCH3), 0.93 (9H, s, 3 x CH3), 0.11 (6H, s, 2 x CH3); 13C NMR (CDCl3) δ:
2-((tert-Butyldimethylsilyl)oxy)-1-(4-
(trifluoromethyl)phenyl)ethanone (3f).17 Yellow solid. Mp 40-42 oC;
44% yield; 1H NMR (CDCl3) δ: 8.04 (2H, d, J = 8.4 Hz, ArH), 7.72 (2H,
4 | J. Name., 2012, 00, 1-3
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197.0, 164.6, 160.9, 132.8, 118.4, 105.4, 98.0, 71.0, 55.5, 55.4, 25.9, dry THF (4.0 mL). The solution was cooled DdoOwI:n10t.1o03-798/C6COaBn0d00N3a6CH
18.6, -5.3; HRMS calcd for C16H26NaO4Si [M+Na]+ 333.1494; found: (60% in oil, 160 mg, 4.00 mmol) was added. The reaction mixture
333.1499.
was stirred for 2 hours at room temperature, filtered using florisil
t
and the solvent removed under vacuum. BuOH (0.5 mL), 2,2,2-
2-((tert-Butyldimethylsilyl)oxy)-1-(furan-2-yl)ethanone
(3l).19 trifluoro-1-phenylethanone (17.4 mg, 0.10 mmol), aqueous buffer
1
Colorless oil. 46% yield; H NMR (CDCl3) δ: 7.61-7.54 (1H, m, ArH), solution (0.5 mL, 0.6M K2CO3 - 4x10-5M EDTA tetrasodium salt),
7.36-7.29 (1H, m, ArH), 6.54-6.51 (1H, m, ArH), 4.73 (2H, s, OCH2), acetonitrile (0.15 mL, 3.00 mmol) and 30% aqueous H2O2 (0.36 mL,
0.91 (9H, s, 3 x CH3), 0.10 (6H, s, 2 x CH3); 13C NMR (CDCl3) δ: 187.0, 3.00 mmol) were added consecutively. After the addition, stirring
150.8, 146.3, 118.0, 112.1, 67.1, 25.8, 18.5, -5.4; MS (ESI) 241 was continued for another
1 hour at room temperature.
(M+H+, 77%).
Subsequently, p-toluenesulfonic acid (350 mg, 2.00 mmol) was
added and the reaction mixture was left stirring for 1 hour at room
2-((tert-butyldimethylsilyl)oxy)-1-(thiophen-2-yl)ethanone (3m). temperature. The crude product was purified using flash column
Yellow oil. 63% yield; 1H NMR (CDCl3) δ: 7.90-7.85 (1H, m, ArH), chromatography (10% EtOAc in Pet. Ether) to afford the desired
7.65-7.62 (1H, m, ArH), 7.14-7.09 (1H, m, ArH), 4.72 (2H, s, OCH2), product.
0.93 (9H, s, 3 x CH3), 0.12 (6H, s, 2 x CH3); 13C NMR (CDCl3) δ: 191.1,
140.5, 133.8, 132.5, 127.8, 68.0, 25.8, 18.4, -5.4; HRMS calcd for
C12H20NaO2SSi [M+Na]+ 279.0845; found: 279.0851.
Representative procedure for 4c-4d, 4f, 4j-4o
Substituted ketone (1.00 mmol) and tert-butylchlorodimethylsilane
(196 mg, 1.30 mmol) were placed in an oven-dried round bottom
flask sealed with a septum, under Ar atmosphere, and dissolved in
2-((tert-Butyldimethylsilyl)oxy)-1-phenylbutan-1-one
(3n).
Colorless oil. After the oxidation, silica (250 mg, 70-230 mesh) was
added and the reaction mixture was left stirring for 1 hour at room
o
dry THF (4.0 mL). The solution was cooled down to -78 C and NaH
1
(60% in oil, 160 mg, 4.00 mmol) was added. The reaction mixture
was stirred for 30 minutes at room temperature, heated under
reflux for 2 hours at 85 oC, filtered using florisil and the solvent
removed under vacuum. tBuOH (0.5 mL), 2,2,2-trifluoro-1-
phenylethanone (17.4 mg, 0.10 mmol), aqueous buffer solution (0.5
mL, 0.6M K2CO3 - 4x10-5M EDTA tetrasodium salt), acetonitrile (0.15
mL, 3.00 mmol) and 30% aqueous H2O2 (0.36 mL, 3.00 mmol) were
added consecutively. After the addition, stirring was continued for 1
hour at room temperature. Subsequently, p-toluenesulfonic acid
(350 mg, 2.00 mmol) was added and the reaction mixture was left
stirring for 1 hour at room temperature. The crude product was
purified using flash column chromatography (10% EtOAc in Pet.
Ether) to afford the desired product.
temperature; 52% yield; H NMR (CDCl3) δ: 8.05 (2H, d, J = 6.9 Hz,
ArH), 7.59-7.36 (3H, m, ArH), 4.67 (1H, dd, J = 7.4 and 5.6 Hz, OCH),
1.91-1.67 (2H, m, CH2), 1.00 (3H, t, J = 7.4 Hz, CH3), 0.87 (9H, s, 3 x
CH3), 0.04 (3H, s, CH3), -0.03 (3H, s, CH3); 13C NMR (CDCl3) δ: 201.6,
135.0, 132.9, 129.2, 128.3, 79.3, 29.1, 25.7, 18.6, 10.2, -5.2; HRMS
calcd for C16H26NaO2Si [M+Na]+ 301.1594; found: 301.1599.
2-((tert-Butyldimethylsilyl)oxy)-2-methyl-1-phenylpropan-1-one
(3o). Yellow oil. After the oxidation, silica (250 mg, 70-230 mesh)
was added and the reaction mixture was left stirring for 1 hour at
1
room temperature; 42% yield; H NMR (CDCl3) δ: 8.17-8.01 (2H, m,
ArH), 7.56-7.28 (3H, m, ArH), 1.58 (6H, s, 2 x CH3), 0.80 (9H, s, 3 x
CH3), 0.05 (3H, s, 2 x CH3); 13C NMR (CDCl3) δ: 203.9, 132.1, 130.2,
128.3, 127.7, 80.4, 29.0, 25.8, 18.1, -2.2; HRMS calcd for
C16H26NaO2Si [M+Na]+ 301.1594; found: 301.1601.
2-Hydroxy-1-phenylethanone (4a).20 White solid. Mp 86-89 oC, 76%
yield; 1H NMR (CDCl3) δ: 7.92 (2H, d, J = 7.1 Hz, ArH), 7.64 (1H, t, J =
7.1 Hz, ArH), 7.51 (2H, t, J = 7.1 Hz, ArH), 4.88 (2H, s, OCH2), 3.38
(1H, br s, OH); 13C NMR (CDCl3) δ: 198.3, 134.1, 133.2, 128.8, 127.5,
65.3; MS (ESI) 137 (M+H+, 81%).
Representative procedure for 4a-4b, 4e, 4g-4i
Substituted ketone (1.00 mmol) and tert-butylchlorodimethylsilane
(196 mg, 1.30 mmol) were placed in an oven-dried round bottom
flask sealed with a septum, under Ar atmosphere, and dissolved in
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2-Hydroxy-1-(p-tolyl)ethanone (4b).21 White solid. Mp 72-74 oC, 7.43 (1H, m, ArH), 7.42-7.27 (2H, m, ArH),D4O.7I:510(2.1H03, 9Vs/i,eCwO6ACOrHtBic02le)0,O03n3.l62inC9e
61% yield; 1H NMR (CDCl3) δ: 7.78 (2H, d, J = 8.2 Hz, ArH), 7.26 (2H, (1H, br s, OH); 13C NMR (CDCl3) δ: 201.4, 136.6, 134.2, 132.8, 129.2,
d, J = 8.2 Hz, ArH), 4.82 (2H, s, OCH2), 3.67 (1H, br s, OH), 2.39 (3H, 127.4, 119.6, 67.7; MS (ESI) 216 (M+H+, 45%).
s, CH3); 13C NMR (CDCl3) δ: 197.8, 145.2, 130.7, 129.5, 127.6, 65.2,
21.7; MS (ESI) 151 (M+H+, 69%).
1-(2-((tert-Butyldimethylsilyl)oxy)phenyl)-2-hydroxyethanone (4i).
1
Yellow oil. 2.6 equiv. of TBDMSCl were added; 50% yield; H NMR
1-([1,1'-Biphenyl]-4-yl)-2-hydroxyethanone (4c).22 White solid. Mp (CDCl3) δ: 7.92 (1H, dd, J = 7.9 and 1.9 Hz, ArH), 7.41 (1H, ddd, J =
o
1
125-127 C, 71% yield; H NMR (CDCl3) δ: 7.97 (2H, d, J = 8.4 Hz, 8.3, 7.9 and 1.9 Hz, ArH), 7.10-6.83 (2H, m, ArH), 4.81 (1H, d, J =
ArH), 7.69 (2H, d, J = 8.4 Hz, ArH), 7.61 (2H, dd, J = 8.0 and 1.5 Hz, 16.8 Hz, OCHH), 4.68 (1H, d, J = 16.8 Hz, OCHH), 0.99 (9H, s, 3 x
ArH), 7.52-7.38 (3H, m, ArH), 4.89 (2H, s, OCH2), 3.63 (1H, br s, OH); CH3), 0.34 (6H, s, 2 x CH3); 13C NMR (CDCl3) δ: 199.5, 156.4, 134.6,
13C NMR (CDCl3) δ: 197.8, 146.8, 139.4, 131.9, 128.9, 128.4, 128.2, 130.8, 125.4, 121.2, 119.8, 69.5, 25.9, 18.7, -3.4; HRMS calcd for
127.4, 127.2, 65.2; MS (ESI) 213 (M+H+, 72%).
C14H22NaO3Si [M+Na]+ 289.1230; found: 289.1236.
2-Hydroxy-1-(naphthalen-2-yl)ethanone (4d).23 White solid. Mp 2-Hydroxy-1-(4-methoxyphenyl)ethanone (4j).22 Pale yellow solid.
1
108-110 °C, 64% yield; H NMR (CDCl3) δ: 8.28 (1H, s, ArH), 7.92- Mp 104-107 oC, 82% yield; 1H NMR (CDCl3) δ: 7.83 (2H, d, J = 9.0 Hz,
7.65 (4H, m, ArH), 7.59-7.38 (2H, m, ArH), 4.96 (2H, s, OCH2); 13C ArH), 6.90 (2H, d, J = 9.0 Hz, ArH), 4.77 (2H, s, OCH2), 3.82 (3H, s,
NMR (CDCl3) δ: 196.3, 135.8, 132.0, 130.2, 129.4, 129.4, 128.8, OCH3); 13C NMR (CDCl3) δ: 196.6, 164.1, 129.8, 126.1, 113.9, 64.8,
128.6, 127.6, 126.8, 122.7, 65.3; MS (ESI) 187 (M+H+, 57%).
55.4; MS (ESI) 167 (M+H+, 77%).
1-(4-Fluorophenyl)-2-hydroxyethanone (4e).21 White solid. Mp 1-(2,4-Dimethoxyphenyl)-2-hydroxyethanone (4k). Yellow solid.
o
1
109-111 C, 57% yield; H NMR (CDCl3) δ: 8.03-7.86 (2H, m, ArH), Mp 127-129 oC, 84% yield; 1H NMR (CDCl3) δ: 7.99 (1H, d, J = 8.8 Hz,
7.16 (2H, t, J = 8.6 Hz, ArH), 4.84 (2H, s, OCH2), 3.65 (1H, br s, OH); ArH), 6.51 (1H, d, J = 8.8 Hz, ArH), 6.39 (1H, s, ArH), 4.65 (2H, s,
13C NMR (CDCl3) δ: 196.8, 166.1 (d, JCF = 254.8 Hz), 132.7 (d, JCF = 9.5 OCH2), 3.85 (3H, s, OCH3), 3.82 (3H, s, OCH3); 13C NMR (CDCl3)
Hz), 129.7 (d, JCF = 3.7 Hz), 115.6 (d, JCF = 22.0 Hz), 65.2; MS (ESI) 155 δ:197.1, 165.7, 162.1, 132.8, 116.0, 105.9, 97.7, 69.2, 55.5, 55.3;
(M+H+, 67%).
HRMS calcd for C10H12NaO4 [M+Na]+ 219.0628; found: 219.0637.
2-Hydroxy-1-(4-(trifluoromethyl)phenyl)ethanone (4f).24 Yellow 1-(Furan-2-yl)-2-hydroxyethanone (4l).26 Yellow solid. Mp 83-85 oC,
o
1
solid. Mp 110-112 C, 42% yield; H NMR (CDCl3:CD3OD 4:1) δ: 7.99 67% yield; 1H NMR (CDCl3) δ: 7.65-7.57 (1H, m, ArH), 7.29-7.25 (1H,
(2H, d, J = 8.2 Hz, ArH), 7.72 (2H, d, J = 8.2 Hz, ArH), 4.87 (2H, s, m, ArH), 6.60-6.54 (1H, m, ArH), 4.71 (2H, s, OCH2), 3.38 (1H, br s,
OCH2), 3.35 (1H, br s, OH); 13C NMR (CDCl3:CD3OD 4:1) δ: 197.7, OH); 13C NMR (CDCl3) δ:187.6, 149.9, 147.0, 117.9, 112.5, 65.0; MS
(ESI) 127 (M+H+, 65%).
136.0, 128.0, 127.6 (q, J = 29.9 Hz), 125.9 (q, J = 3.7 Hz), 123.0 (q, J =
248.2 Hz), 65.6; 19F NMR (CDCl3) δ: 15.6; MS (ESI) 205 (M+H+, 71%).
2-Hydroxy-1-(thiophen-2-yl)ethanone (4m).27 Brown oil. 78% yield;
1-(4-Bromophenyl)-2-hydroxyethanone (4g).25 Colorless solid. Mp
1H NMR (CDCl3:CD3OD 4:1) δ: 7.76-7.67 (2H, m, ArH), 7.14-7.06 (1H,
o
1
103-104 C, 65% yield; H NMR (DMSO) δ: 7.81 (2H, d, J = 8.5 Hz,
ArH), 7.68 (2H, d, J = 8.5 Hz, ArH), 4.74 (2H, s, OCH2), 3.36 (1H, br s,
OH); 13C NMR (DMSO) δ: 198.5, 133.5, 131.8, 129.6, 127.4, 65.3; 19F
NMR (CDCl3) δ: -23.1; MS (ESI) 216 (M+H+, 48%).
m, ArH), 4.74 (2H, s, OCH2); 13C NMR (CDCl3:CD3OD 4:1) δ: 191.7,
139.6, 134.8, 132.4, 128.7, 65.6; MS (ESI) 143 (M+H+, 59%).
2-Hydroxy-1-phenylbutan-1-one (4n).28 Colorless oil. 50% yield;
After the oxidation silica (250 mg, 70-230 mesh) was added and the
reaction mixture was left stirring for 1 hour at room temperature;
1H NMR (CDCl3) δ: 7.90 (2H, d, J = 7.1 Hz, ArH), 7.59 (1H, d, J = 7.1
1-(2-Bromophenyl)-2-hydroxyethanone (4h).21 White low melting
solid. 57% yield; 1H NMR (CDCl3) δ: 7.69-7.56 (1H, m, ArH), 7.55-
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Hz, ArH), 7.49 (2H, d, J = 7.1 Hz, ArH), 5.05 (1H, dd, J= 6.8 and 3.9 6 a) G. M. Rubottom, M. I. L. Nieves, TetrDaOheI:d1r0o.1n03L9Ve/ietCwt6.AO1rtB9ic07le02O0,n31l6in3Ce
,
Hz, OCH), 3.79 (1H, br s, OH), 2.06-1.81 (1H, m, CHH), 1.70-1.49 (1H,
m, CHH), 0.92 (3H, t, J = 7.4 Hz, CH3); 13C NMR (CDCl3) δ: 202.0,
133.8, 133.7, 128.7, 128.4, 73.8, 28.7, 8.7; MS (ESI) 165 (M+H+,
76%).
2423; b) E. Friedrich, W. Lutz, Angew. Chem., Int. Ed. Engl.
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50% yield; After the oxidation silica (250 mg, 70-230 mesh) was
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added and the reaction mixture was left stirring for 1 hour at room
1
temperature; H NMR (CDCl3) δ: 8.17-7.92 (2H, m, ArH), 7.63-7.35 9 G. M. Rubottom, J. M. Gruber, J. Org. Chem. 1978, 43, 1599.
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(M+H+, 81%).
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