Synthesis of α-hydroxyacetophenones

Article abstract of DOI:10.1021/jo3005556

A general method for the preparation of α-hydroxyacetophenones is presented. Functionalized arylmagnesium species are transmetalated to the corresponding arylzinc intermediates, which undergo Cu(I)-catalyzed reaction with acetoxyacetyl chloride. Acidic hy

Full text of DOI:10.1021/jo3005556

Note
pubs.acs.org/joc
Synthesis of α-Hydroxyacetophenones
Mark McLaughlin,* Kevin M. Belyk, Gang Qian, Robert A. Reamer, and Cheng-yi Chen
Department of Process Research, Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: A general method for the preparation of α-hydroxyacetophenones is
presented. Functionalized arylmagnesium species are transmetalated to the
corresponding arylzinc intermediates, which undergo Cu(I)-catalyzed reaction with
acetoxyacetyl chloride. Acidic hydrolysis of the acetate group releases the target α-
hydroxyacetophenones with minimal production of undesired polymeric degradates
that are often observed under alternative conditions.
α-Hydroxyacetophenones are useful synthetic intermediates
amenable to various asymmetric transformations capable of
generating valuable chiral compounds.1 A number of methods
for the preparation of α-hydroxyacetophenones have been
described in the literature. Acetophenones can be oxidized
directly to 2-hydroxyacetophenones or indirectly via oxidation
of the corresponding silyl enol ethers.2 Alternatively,
acetophenones can be halogenated at the α-position and then
subjected to nucleophilic displacement and in situ solvolysis/
hydrolysis to provide α-hydroxyacetophenones.3 Another
procedure utilizing α-bromoacetophenones involves nucleo-
philic displacement with acetate followed by enzymatic cleavage
of the resulting α-acetoxyacetophenones.4 Enzyme-mediated
hydroxymethylation of benzaldehydes has also been reported.5
Hydroxymethylation via chemocatalysis (N-heterocyclic car-
benes) is also known.6 Epoxides and 1,2-diols derived from
styrenes can be further oxidized to yield α-hydroxyacetophe-
nones.7,8 α-diazoacetophenones can be hydrolyzed under acidic
conditions to provide α-hydroxyacetophenones.9 In this paper,
we present a convenient method for the preparation of α-
hydroxyacetophenones that allows flexibility and control with
regard to the substituents on the aromatic ring.
followed by transmetalation to the arylzinc reagent as our
standard method.14,15
Optimization of the stoichiometry for the preparation of α-
acetoxyacetophenones using 1a is shown in Table 1. Initially,
Table 1. Optimization of α-Acetoxyacetophenone Synthesis
entry
ZnCl2 (equiv)
CuCl (equiv)
AY (%)
1
2
3
4
1
0.1
85
83
82
83
1
0.05
0.01
0.01
1
0.5
using 1 equiv of ZnCl2 and 10 mol % of CuCl led to an assay
yield of 85% for 2a. Attempts to reduce the loading of CuCl
required for this reaction established that 1 mol % of CuCl was
adequate to achieve similar results.16 Last, it was shown that
using only 0.5 equiv of ZnCl2 had no detrimental effect on
yield, and these conditions were selected as standard for
preparation of other substrates.17
At the outset of our studies, we envisaged a two-step
sequence involving direct acylation10 of arylzinc intermediates
to form α-acetoxyacetophenones, followed by deprotection of
the acetate group (Figure 1). An important feature of this
As shown in Table 2, application of the general procedure to
a series of diversely functionalized aryl iodides and bromides
generally afforded moderate to good yields of the desired α-
acetoxyacetophenones (2a−k). Of particular note are examples
where Friedel−Crafts processes would afford alternative or
limited regioselection. In most cases, the products were isolated
as crystalline solids in high purity following standard aqueous
workup and crystallization from an appropriate solvent mixture
(typically heptane/MTBE). For certain products that would
not crystallize, silica chromatography could be used to isolate
analytically pure material.
Figure 1. Proposed synthesis of α-hydroxyacetophenones.
approach is the ability to incorporate highly functionalized
aromatic nucleophiles that are readily available via one of
several elegant procedures developed by Knochel.11−13 It is also
worth noting that this strategy leads to well-defined and in
some cases alternative regioselectivity to that expected from
Friedel−Crafts reaction between acid chlorides and arenes. For
reasons of practicality, we selected Mg−X exchange chemistry
Received: March 15, 2012
Published: May 8, 2012
© 2012 American Chemical Society
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Note
Table 2. Synthesis of α-Acetoxyacetophenones
Having secured access to the intermediate α-acetoxyaceto-
phenones, attention was turned to the development of
conditions for unmasking the desired 2-hydroxacetophenones.
Although this transformation appears trivial, certain reactivity
features exhibited by this class of compound preclude the use of
commonly applied conditions for acetate deprotection. Our
initial attempt to cleave the acetate ester under relatively
standard K2CO3/MeOH conditions resulted in the formation
of multiple products, confirming our suspicion that these
compounds are intolerant of basic conditions. Presumably, this
is due to the acidity of the methylene group and subsequent
phenones into the corresponding formate ester via nucleophilic
displacement using sodium formate followed by in situ
hydrolysis/solvolysis under nonbasic conditions. It is noted in
this report that “nucleophiles other than formate such as acetate
or hydroxide are not desirable for the synthesis of α-
hydroxyacetophenones”. Although these conditions are close
to neutral pH, application to substrates of interest at Merck still
led to significant polymerization/degradation and difficulties in
isolating the products without recourse to chromatography.
With these results in mind, we examined the use of acidic
conditions for acetate deprotection in the hope that better
results could be obtained.19 Following some experimentation, it
was found that α-acetoxyacetophenones can be deprotected at
low pH without the extensive degradation observed under basic
uncontrolled reactivity of the resulting enolate species.18
A
literature method3 for the synthesis of α-hydroxyacetophenones
recommends conversion of separately prepared α-bromoaceto-
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conditions. Treatment of the α-acetoxyacetophenones with 5 N
aqueous HCl at 40 °C, using MeOH as a cosolvent to aid
solubility, leads to cleavage of the acetate group within 3−6 h.
It was observed that the hydroxyketone products are relatively
sensitive to oxygen when in solution, presumably via facile
oxidation of equilibrium concentrations of the enol tautomer.
For this reason, best results are obtained when the hydrolysis is
conducted under a nitrogen atmosphere. Notably, under these
conditions the formation of polymeric degradates is minimized
and assay yields of the α-hydroxyketones are generally good. In
most cases the product can be isolated by direct crystallization
after dilution of the reaction mixture with additional water.
Table 3 presents yields for the preparation of a range of α-
hydroxyacetophenones via acetate cleavage under the devel-
oped acidic conditions. Substrates bearing potentially sensitive
functional groups such as nitrile or ethyl ester are tolerated,
although for the latter case EtOH is used in place of MeOH to
avoid transesterification.
Table 3. Synthesis of α-Hydroxyacetophenones
The ability to avoid isolation of intermediates when
conducting multikilogram-scale synthesis is often desirable
since this operation can be time/resource consuming. Through-
processing of the crude product from a reaction can be more
efficient on large scale so the direct preparation of α-
hydroxyacetophenones without isolating the intermediate α-
acetoxyacetophenones was investigated. To our satisfaction, it
was indeed possible to achieve this, and Figure 2 displays the
results from implementation of this procedure on 100 g scale
for the conversion of 1a into 3a.
In summary, we have described a straightforward approach to
the synthesis of α-hydroxyketones that employs simple
procedures and commercially available reagents. By utilizing
mild conditions to generate functionalized organometallic
species (Mg-X exchange) it is possible to prepare α-
acetoxyacetophenones substituted at various positions on the
aromatic ring with interesting functional handles. Significantly,
we have shown that the target α-hydroxyacetophenones can be
unmasked under acidic hydrolysis conditions that do not cause
extensive degradation and are tolerated by potentially sensitive
functional groups. Although α-hydroxyacetophenones have
featured many times in the chemical literature, the apparent
absence of reports focused on general procedures for their
preparation is perhaps indicative of underlying issues associated
with these intermediates. In this regard, the method presented
in this paper may be of use for the synthesis of this useful class
of organic compounds.
EXPERIMENTAL SECTION
■
Screening reactions were conducted under a nitrogen atmosphere in 8
mL vials equipped with magnetic stir-bars and septa. Larger scale
preparative reactions were conducted in standard round-bottom flasks
under a nitrogen atmosphere. HPLC-grade solvents were used with no
additional purification/drying. All other reagents were standard grade
and used without further purification. Reaction conversion and assay
yields were monitored using reversed-phase HPLC with reference to
purified standards for quantification purposes. NMR spectra were
1
recorded using 400 and 500 MHz spectrometers; H NMR recorded
at 400 and 500 MHz and 13C recorded at 100 or 125 MHz. High-
resolution mass data were obtained using electrospray ionization
(positive ion mode). Flash column chromatography was performed
using a robotic instrument fitted with an appropriately sized silica
cartridge.
Figure 2. α-Hydroxyacetophenone through-process.
nitrogen inlet, and temperature probe was charged with i-PrMgCl·LiCl
(14 wt % in THF, 9.9 mL, 10.0 mmol, 1 equiv). Neat 1-bromo-3,5-
difluorobenzene 1a (1.93 g, 10.0 mmol, 1 equiv) was added dropwise
via syringe at 20−30 °C over 10 min, and the Mg−Br exchange was
complete within 1 h as monitored via quenching a sample into MeOH
General Procedure for Synthesis of α-Acetoxyacetophe-
nones (2). Representative Procedure for the Synthesis of α-
Acetoxyacetophenones: Synthesis of 1-(3,5-Difluorophenyl)-α-ace-
toxyethanone. A 40 mL vial equipped with a septum cap, stir bar,
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for reversed-phase HPLC analysis. The resultant solution of ArMgX
was cooled to 0 °C and subjected to transmetalation via treatment
with ZnCl2 (0.5 M in THF, 10.0 mL, 0.5 equiv), maintaining <20 °C.
To the resultant solution was added CuCl (9.9 mg, 0.1 mmol, 1 mol
%) followed by neat acetoxyacetyl chloride (1.18 mL, 11.0 mmol, 1.1
equiv) dropwise via syringe, maintaining <30 °C. The cooling bath was
removed, and the resultant solution was aged until conversion of the
ArMgX species was observed via reversed-phase HPLC analysis. The
solution was poured into 2 M aqueous HCl (30 mL) and extracted
with MTBE (75 mL). The organic phase was washed with brine (30
mL) and then dried over Na2SO4, filtered, and concentrated under
reduced pressure. The solvent was eventually switched to heptane,
causing crystallization of the α-acetoxyacetophenone, which was
collected by filtration. 1-(3,5-Difluorophenyl)-α-acetoxyethanone 2a
was obtained as a white solid.
General Procedure for Synthesis of α-Hydroxyacetophe-
nones (3). Representative α-acetoxyacetophenone hydrolysis proce-
dure: A mixture of 1-(3,5-difluorophenyl)-α-acetoxyethanone 2a (1.19
g, 5.0 mmol, 1 equiv), MeOH (6 mL), and 5 M aqueous HCl (6 mL,
30.0 mol, 6 equiv) was heated at 40 °C under a nitrogen atmosphere
for 4−6 h, after which time HPLC analysis indicated complete
conversion of the acetate. The orange mixture was concentrated under
reduced pressure to remove the MeOH, causing crystallization of the
desired hydroxyketone. The final aqueous slurry was cooled to 0−5 °C
for 1 h before the solid was collected by filtration and rinsed with
water. 1-(3,5-Difluorophenyl)-α-hydroxyethanone 3a was obtained as
an orange solid.
4-(α-Acetoxyacetyl)benzoic Acid Ethyl Ester (2g). Following the
general procedure, 2g was obtained as a white solid: 1.57 g (63%); 1H
NMR (500 MHz, CDCl3) δ 1.45 (t, J = 7.2 Hz, 3H), 2.26 (s, 3H), 4.45
(q, J = 7.2 Hz, 2H), 5.37 (s, 2H), 7.99 (d, J = 8.3 Hz, 2H), 8.18 (d, J =
8.3 Hz, 2H); 13C {1H} NMR (125 MHz, CDCl3) δ 14.2, 20.5, 61.5,
66.1, 127.7, 130.0, 135.0, 137.3, 165.4, 170.3, 191.9; HRMS calcd for
C13H15O5 (M + H) 251.0919, found 251.0916.
α-Acetoxy-4-chloroacetophenone (2h): Following the general
procedure, 2h was obtained as a white solid: 1.17 g (55%); 1H
NMR (400 MHz, CDCl3) δ 2.23 (s, 3H), 5.29 (s, 2H), 7.46 (d, J = 8.5
Hz, 2H), 7.85 (d, J = 8.5 Hz, 2H); 13C {1H} NMR (100 MHz, CDCl3)
δ 20.5, 65.9, 129.2, 129.3, 132.6, 140.4, 170.4, 191.8; HRMS calcd for
C10H10ClO3 (M + H) 213.0318, found 213.0316.
α-Acetoxy-4-methylacetophenone (2i). Following the general
1
procedure, 2i was obtained as a white solid: 1.19 g (62%); H NMR
(400 MHz, CDCl3) δ 2.23 (s, 3H), 2.42 (s, 3H), 5.31 (s, 2H), 7.27 (d,
J = 8.2 Hz, 2H), 7.81 (d, J = 8.2 Hz, 2H); 13C {1H} NMR (100 MHz,
CDCl3) δ 20.6, 21.7, 65.9, 127.9, 129.5, 131.8, 144.9, 170.4, 191.4;
HRMS calcd for C11H13O3 (M + H) 193.0865, found 193.0861.
α-Acetoxy-2-fluoroacetophenone (2j). Following the general
1
procedure, 2j was obtained as a white solid: 1.41 g (82%); H NMR
(500 MHz, CDCl3) δ 2.25 (s, 3H), 5.25 (s, 2H), 7.17−7.22 (m, 1H),
7.28−7.33 (m, 1H), 7.58−7.64 (m, 1H), 7.98−8.02 (m, 1H); 13C
{1H} NMR (125 MHz, CDCl3) δ 20.5, 69.1 (d, JCF = 15 Hz), 116.5
(d, JCF = 24 Hz), 122.4 (d, JCF = 14 Hz), 124.8 (d, JCF = 4 Hz), 130.7
(d, JCF = 4 Hz), 135.6 (d, JCF = 9 Hz), 162.3 (d, JCF = 254 Hz), 170.3,
190.4 (d, JCF = 20 Hz); HRMS calcd for C10H10FO3 197.0614, found
197.0611.
α-Acetoxy-4-fluoroacetophenone (2k). Following the general
procedure, 2k was obtained as a white solid: 1.41 g (82%); 1H
NMR (500 MHz, CDCl3) δ 2.25 (s, 3H), 5.32 (s, 2H), 7.16−7.21 (m,
2H), 7.95−7.99 (m, 2H); 13C {1H} NMR (125 MHz, CDCl3) δ 20.5,
65.8, 116.1 (d, JCF = 22 Hz), 130.5 (d, JCF = 10 Hz), 130.7 (d, JCF = 3
Hz), 166.1 (d, JCF = 256 Hz), 170.4, 190.7; HRMS calcd for
C10H10FO3 (M + H) 197.0614, found 197.0610.
α-Hydroxy-3,5-difluoroacetophenone (3a): Following the general
procedure, 3a was obtained as a white solid: 0.74 g (86%); mp 95−97
°C; 1H NMR (500 MHz, CDCl3) δ 3.42 (br, 1H), 4.85 (s, 2H), 7.07−
7.13 (m, 1H), 7.41−7.47 (m, 2H); 13C {1H} NMR (125 MHz,
CDCl3) δ 65.7, 109.5 (t, JCF = 26 Hz) 110.7 (m), 136.1 (t, JCF = 8 Hz),
163.2 (dd, JCF = 252, 12 Hz), 196.4; HRMS calcd for C8H7F2O2 (M +
H) 173.0414, found 173.0406.
α-Acetoxy-3,5-difluoroacetophenone (2a). Following the general
procedure, 2a was obtained as a white solid: 1.58 g (74%); mp 70−73
°C; 1H NMR (500 MHz, CDCl3) δ 2.25 (s, 3H), 5.28 (s, 2H), 7.07−
7.11 (m, 1H), 7.41−7.47 (m, 2H); 13C {1H} NMR (125 MHz,
CDCl3) δ 20.4, 65.8, 109.2 (t, JCF = 26 Hz) 110.9 (m), 136.9 (t, JCF
=
8 Hz), 163.2 (dd, JCF = 252, 12 Hz), 170.2, 190.2; HRMS calcd for
C10H9F2O3 (M + H) 215.0520, found 215.0519.
α-Acetoxy-3-methoxyacetophenone (2b). Following the general
1
procedure, 2b was obtained as a white solid: 1.41 g (68%); H NMR
(500 MHz, CDCl3) δ 2.27 (s, 3H), 3.88 (s, 3H), 5.35 (s, 2H), 7.16−
7.19, (m, 1H), 7.39−7.43 (m, 1H), 7.46−7.51 (m, 2H); 13C {1H}
NMR (125 MHz, CDCl3) δ 20.6, 55.5, 66.1, 112.1, 120.2, 120.4, 129.9,
160.0, 170.4, 192.0; HRMS calcd for C11H13O4 (M + H) 209.0814,
found 209.0813.
α-Acetoxy-3-fluoroacetophenone (2c). Following the general
procedure, 2c was obtained as a white solid: 1.14 g (85%); mp 91−
α-Hydroxy-3-methoxyacetophenone (3b). Following the general
1
1
93 °C; H NMR (500 MHz, CDCl3) δ 2.20 (s, 3H), 5.18 (s, 2H),
procedure, 3b was obtained as a white solid: 0.65 g (78%); H NMR
7.34−7.40 (m, 1H), 7.42−7.47 (m, 1H), 7.52−7.56 (m, 1H), 7.64−
7.67 (m, 1H); 13C {1H} NMR (125 MHz, CDCl3) δ 20.4, 67.7, 119.1,
127.6, 129.3, 132.5, 133.8, 138.2, 170.2, 196.4; HRMS calcd for (M +
H) C10H10BrO3 256.9813, found 256.9806.
α-Acetoxy-3-cyanoacetophenone (2d). Following the general
procedure, 2d was obtained as a white solid: 1.10 g (54%); 1H
NMR (500 MHz, CDCl3) δ 2.26 (s, 3H), 5.33 (s, 2H), 7.67 (t, J = 8.2
Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 8.22 (s,
1H); 13C {1H} NMR (125 MHz, CDCl3) δ 20.5, 65.8, 113.6, 117.6,
130.0, 131.5, 131.7, 135.1, 136.7, 170.3, 190.6; HRMS calcd for
C11H10NO3 (M + H) 204.0661, found 204.0661.
(400 MHz, CDCl3) δ 3.55 (br, 1H), 3.88 (s, 3H), 4.87 (s, 2H), 7.13−
7.19, (m, 1H), 7.38−7.44 (m, 1H), 7.46−7.49 (m, 2H); 13C {1H}
NMR (125 MHz, CDCl3) δ 55.5, 65.5, 112.1, 120.1, 120.6, 129.9,
134.7, 160.0, 198.3; HRMS calcd for C9H11O3 (M + H) 167.0708,
found 167.0712.
α-Hydroxy-2-bromoacetophenone (3c): Following the general
1
procedure, 3c was obtained as a white solid: 0.83 g (77%); H NMR
(500 MHz, CDCl3) δ 3.40 (br, 1H), 4.78 (s, 2H), 7.35−7.43 (m, 2H),
7.51−7.54 (m, 1H), 7.64−7.67 (m, 1H); 13C {1H} NMR (125 MHz,
CDCl3) δ 68.0, 119.9, 127.6, 129.4, 133.0, 134.4, 136.8, 201.6; HRMS
calcd for C8H8BrO2 (M + H) 214.9708, found 214.9706.
α-Acetoxy-3-bromoacetophenone (2e). Following the general
procedure, 2e was obtained as a white solid: 1.64 g (64%); 1H
NMR (500 MHz, CDCl3) δ 2.26 (s, 3H), 5.31 (s, 2H), 7.39−7.42 (m,
1H), 7.76−7.78 (m, 1H), 7.84−7.87 (m, 1H), 8.06−8.08 (m, 1H); 13C
{1H} NMR (125 MHz, CDCl3) δ 20.5, 65.9, 123.2, 126.3, 130.5,
130.9, 135.9, 136.7, 170.3, 191.0; HRMS calcd for C10H10BrO3 (M +
H) 256.9813, found 256.9815.
α-Hydroxy-3-cyanoacetophenone (3d): Following the general
procedure, 3d was obtained as a white solid: 0.49 g (61%); 1H
NMR (500 MHz, CDCl3) δ 3.38 (br, 1H), 4.93 (s, 2H), 7.69 (t, J =
8.1 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 8.23 (s,
1H); 13C {1H} NMR (125 MHz, CDCl3) δ 65.7, 113.7, 117.5, 130.1,
131.4, 131.6, 134.3, 137.0, 196.8; HRMS calcd for C9H8NO2 (M + H)
162.0555, found 162.0551.
α-Acetoxy-4-cyanoacetophenone (2f): Following the general
procedure, 2f was obtained as a white solid: 1.22 g (60%); mp
α-Hydroxy-3-bromoacetophenone (3e): Following the general
procedure, 3e was obtained as a white solid: 0.88 g (82%); H NMR
1
1
102−104 °C: H NMR (500 MHz, CDCl3) δ 2.23 (s, 3H), 5.32 (s,
(500 MHz, CDCl3) δ 3.40 (br, 1H), 4.88 (s, 2H), 7.40−7.45 (m, 1H),
7.76−7.79 (m, 1H), 7.83−7.86 (m, 1H), 8.08 (s, 1H); 13C {1H} NMR
(125 MHz, CDCl3) δ 65.6, 123.3, 126.2, 130.6, 130.8, 135.1, 137.1,
197.3; HRMS calcd for C8H8BrO2 (M + H) 214.9708, found
214.9714.
2H), 7.81 (d, J = 8.0 Hz, 2H), 8.02 (d, J = 8.0 Hz, 2H); 13C {1H}
NMR (125 MHz, CDCl3) δ 20.4, 65.9, 117.2, 117.6, 128.3, 132.7,
137.2, 170.3, 191.3; HRMS calcd for C11H10NO3 (M + H) 204.0661,
found 204.0663.
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α-Hydroxy-4-cyanoacetophenone (3f). Following the general
procedure, 3f was obtained as a white solid: 0.53 g (66%); H NMR
M.; Hou, K.-C.; Prakash, I.; Arora, S. K. Organic Synthesis; Wiley: New
York, 1993; Collect. Vol. VIII, p 132. Oxidation of silyl ether:
(d) Moriarty, R. M.; Prakash, O.; Duncan, M. P. Synthesis 1985, 943−
944. (e) Le, J. C.-D.; Pagenkopf, B. L. J. Org. Chem. 2004, 69, 4177−
4180.
1
(500 MHz, CDCl3) δ 3.37 (br, 1H), 4.93 (s, 2H), 7.84 (d, J = 8.0 Hz,
2H), 8.04 (d, J = 8.0 Hz, 2H); 13C {1H} NMR (125 MHz, CDCl3) δ
65.9, 117.6, 128.2, 132.8, 136.4, 197.4; HRMS calcd for C9H8NO2 (M
+ H) 162.0555, found 162.0553.
4-(α-Hydroxyacetyl)benzoic Acid Ethyl Ester (3g). Following the
general procedure, 3g was obtained as a white solid: 0.89 g (85%); 1H
NMR (400 MHz, CDCl3) δ 1.45 (t, J = 7.2 Hz, 3H), 3.47 (br, 1H),
4.45 (q, J = 7.2 Hz, 2H), 4.93 (s, 2H), 7.99 (d, J = 8.3 Hz, 2H), 8.20
(d, J = 8.3 Hz, 2H); 13C {1H} NMR (125 MHz, DMSO) δ 14.6, 61.7,
66.2, 128.4, 129.8, 134.1, 135.5, 165.5, 199.5; HRMS calcd for
C11H13O4 (M + H) 209.0814, found 209.0806.
(3) (a) Zhu, G.; Casalnuovo, A. L.; Zhang, X. J. Org. Chem. 1998, 63,
8100−8101. (b) Wong, F. F.; Chang, P.-W.; Lin, H.-C.; You, B.-J.;
Huang, J.-J.; Lin, S.-K. J. Organomet. Chem. 2009, 694, 3452−3455.
́ ́
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D.; Poppe, L. J. Chem. Soc., Perkin Trans. 1 2002, 2400−2402.
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2004, 60, 6509−6512.
(6) Kuhl, N.; Glorious, F. Chem. Commun. 2011, 47, 573−575.
(7) Via epoxides: Reddy, M. A.; Banumathi, N.; Rao, K. R.
Tetrahedron Lett. 2002, 43, 3237−3238.
α-Hydroxy-4-chloroacetophenone (3h). Following the general
1
procedure, 3h was obtained as a white solid: 0.73 g (86%); H NMR
(400 MHz, CDCl3) δ 3.43 (br, 1H), 4.85 (s, 2H), 7.49 (d, J = 8.2 Hz,
2H), 7.87 (d, J = 8.2 Hz, 2H); 13C {1H} NMR (100 MHz, CDCl3) δ
65.4, 129.1, 129.4, 131.7, 140.8, 197.3; HRMS calcd for C8H8ClO2 (M
+ H) 171.0213, found 171.0211.
(8) (a) Kang, S. K.; Jung, K. Y.; Park, C. H.; Namkoong, E. Y.; Kim,
T. H. Tetrahedron Lett. 1995, 36, 6287. (b) Morimoto, T.; Hirano, M.;
Iwasaki, K.; Ishikawa, T. Chem. Lett. 1994, 53. (c) Macrouhi, F.; Namy,
J. L.; Kagan, H. B. Tetrahedron Lett. 1997, 38, 7183. (d) Filler, R.
Chem. Rev. 1963, 63, 21.
α-Hydroxy-4-methylacetophenone (3i). Following the general
1
procedure, 3i was obtained as a white solid: 0.58 g (77%); H NMR
(9) (a) Muthusamy, S.; Babu, S. A.; Gunanathan, C.; Jasra, R. V.
Synlett 2002, 407−410. (b) Muthusamy, S.; Babu, S. A.; Gunanathan,
C.; Jasra, R. V. Tetrahedron Lett. 2001, 42, 5113−5116.
(400 MHz, CDCl3) δ 2.43 (s, 3H), 3.54 (br, 1H), 4.84 (s, 2H), 7.30
(d, J = 8.0 Hz, 2H), 7.82 (d, J = 8.0 Hz, 2H); 13C {1H} NMR (100
MHz, CDCl3) δ 21.8, 65.3, 127.8, 129.6, 130.9, 145.4, 197.9; HRMS
calcd for C9H11O2 151.0759, found 151.0763.
(10) For related work also from these laboratories, see: Rosen., J.;
Steinhuebel, D.; Palucki, M.; Davies, I. W. Org. Lett. 2007, 9, 667−669.
(11) For reviews on Mg−X exchange, see: (a) Ila, H.; Baron, O.;
Wagner, A. J.; Knochel, P. Chem. Commun. 2006, 6, 583−593.
(b) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp,
F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42,
4302−4320. (c) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P.
Angew. Chem., Int. Ed. 2000, 39, 4415−4435.
α-Hydroxy-2-fluoroacetophenone (3j). Following the general
1
procedure, 3j was obtained as a white solid: 0.62 g (81%); H NMR
(500 MHz, CDCl3) δ 3.62 (br, 1H), 4.81 (s, 2H), 7.17−7.22 (m, 1H),
7.28−7.33 (m, 1H), 7.59−7.64 (m, 1H), 8.05−8.09 (m, 1H); 13C
{1H} NMR (125 MHz, CDCl3) δ 69.3 (d, JCF = 15 Hz), 116.8 (d, JCF
= 23 Hz), 121.6 (d, JCF = 13 Hz), 124.8 (d, JCF = 3 Hz), 130.6 (d, JCF
=
3 Hz), 135.9 (d, JCF = 9 Hz), 162.8 (d, JCF = 256 Hz), 196.9 (d, JCF = 5
Hz); HRMS calcd for C8H8FO2 (M + H) 155.0508, found 155.0507.
α-Hydroxy-4-fluoroacetophenone (3k). Following the general
procedure, 3k was obtained as a white solid: 0.61 g (79%): 1H
NMR (500 MHz, CDCl3) δ 3.50 (br, 1H), 4.87 (s, 2H), 7.19−7.23
(m, 2H), 7.97−8.01 (m, 2H); 13C {1H} NMR (125 MHz, CDCl3) δ
65.3, 116.2 (d, JCF = 22 Hz), 129.9 (d, JCF = 3 Hz), 130.4 (d, JCF = 10
Hz), 166.4 (d, JCF = 256 Hz), 196.8; HRMS calcd for C8H8FO2 (M +
H) 155.0508, found 155.0506.
(12) For recent examples of the direct preparation of functionalized
arylzinc intermediates, see: Krasovskiy, A.; Malakhov, V.; Gavryushin,
A.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 6040−6044.
(13) For the direct preparation of functionalized arylmagnesium
intermediates, see: Piller, F. M.; Appukkuttan, P.; Gavryushin, A.;
Helm, M.; Knochel, P. Angew. Chem., Int. Ed. 2008, 47, 6802−6806.
(14) Direct preparation of the requisite arylzinc intermediates would
ultimately be more efficient, but the use of commercial i-PrMgCl·LiCl
and ZnCl2 solutions was deemed more user-friendly in the short term.
Additionally, the use of i-PrMgCl·LiCl rather than i-PrMgCl led to
more predictable and better results for Mg−X exchange for the
substrates studied here.
(15) As a control, direct reaction between ArMgX and acetoxyacetyl
chloride was studied, but this led to low yields of the desired ketone.
(16) No reaction was observed in the absence of a Cu additive.
(17) Cu-catalyzed acylation of the ArMgX without prior trans-
metalation using ZnCl2 was also studied. This more direct approach is
successful with certain substrates and significantly simplifies the
experimental procedure, however the desired product is usually
contaminated with 5−10% of the tertiary alcohol resulting from
overaddition.
ASSOCIATED CONTENT
* Supporting Information
NMR spectra for all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: mark_mclaughlin@merck.com.
■
Notes
The authors declare no competing financial interest.
(18) This facility of enolization was also observed during attempts to
hydrogenolize O-benzyl protected α-hydroxyacetophenones, where
the primary product obtained was the 2-benzyloxy-1-phenyl-ethanol
derivative, resulting from hydrogenation of the enol carbon-carbon
double bond.
(19) In-house experience with the HCl promoted cleavage of O-THP
protected α-hydroxyacetophenones indicated that the desired products
were relatively stable under aqueous HCl conditions.
ACKNOWLEDGMENTS
High resolution mass spectroscopy analysis support from
Thomas J. Novak is gratefully acknowledged.
■
REFERENCES
■
(1) For example: Asymmetric hydrogenation affording 1,2-diols:
(a) Ohkuma, T.; Utsumi, N.; Watanabe, M.; Arai, N.; Murata, K. Org.
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affording β-amino alcohols: Matsunaga, S.; Kumagai, N.; Harada, S.;
Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 4712−4713. (c) Trost, B.
M.; Jaratjaroonphong, J.; Reutrakul, V. J. Am. Chem. Soc. 2006, 128,
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(2) Direct oxidation: (a) Moriarty, R. M.; Berglund, B. A.; Penmasta,
R. Tetrahedron Lett. 1992, 33, 6065−6068. (b) Chen, C.; Feng, X.;
Zhang, G.; Zhao, Q.; Huang, G. Synthesis 2008, 3205. (c) Moriarty, R.
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