Palladium-catalyzed cross-coupling of sterically demanding boronic acids with α-bromocarbonyl compounds

Article abstract of DOI:10.1021/jo2014998

A catalyst system generated in situ from Pd(dba)₂ and tri(o-tolyl)phosphine mediates the coupling of arylboronic acids with alkyl α-bromoacetates under formation of arylacetic acid esters at unprecedented low loadings. The new protocol, which involves potassium fluoride as the base and catalytic amounts of benzyltriethylammonium bromideas a phase transfer catalyst, is uniquely effective for the synthesis of sterically demanding arylacetic acid derivatives. (Figure presented)

Full text of DOI:10.1021/jo2014998

NOTE
pubs.acs.org/joc
Palladium-Catalyzed Cross-Coupling of Sterically Demanding Boronic
Acids with α-Bromocarbonyl Compounds
Bettina Zimmermann,† Wojciech I. Dzik,† Thomas Himmler,‡ and Lukas J. Goossen*,†
†Department of Organic Chemistry, Technische Universit€at Kaiserslautern, Erwin-Schroedinger-Str. Geb. 54, 67663 Kaiserslautern,
Germany
‡Bayer CropScience AG, Alfred-Nobel-Str. 50, 40789 Monheim am Rhein, Germany
S Supporting Information
b
ABSTRACT: A catalyst system generated in situ from Pd(dba)2
and tri(o-tolyl)phosphine mediates the coupling of arylboronic
acids with alkyl α-bromoacetates under formation of arylacetic
acid esters at unprecedented low loadings. The new protocol,
which involves potassium fluoride as the base and catalytic
amounts of benzyltriethylammonium bromide as a phase transfer
catalyst, is uniquely effective for the synthesis of sterically
demanding arylacetic acid derivatives.
any α-arylacetic acid derivatives display unique biological
1-naphthylphosphine, 5 equiv of K3PO4, 20 °C), and the reported
examples include ortho-substituted and halogen-substituted aryl-
acetates.11a However, when we applied them to the reaction of
ethyl bromoacetate with the o,o-disubstituted 2,6-dimethylphe-
nylboronic acid, we observed no formation to the desired ethyl
2-(2,6-dimethylphenyl)acetate (Scheme 1). The alternative nick-
el-based system11c also proved to be ineffective for such bulky
substrates. The only catalyst system for which a successful coupling
of an o,o-disubstituted arylboronic acid with an alkyl bromoace-
tate has been reported calls for taylor-made aminophosphine
ligands,11d and we were reluctant to base our synthetic strategy
on commercially unavailable catalysts.
We thus set out to develop a catalytic system that would use
cheap and readily accessible ligands and be active enough to
mediate the title reaction with catalyst loadings that are sub-
stantially lower than the 3 mol % required for the known
protocols.
M
and pharmaceutical activities.1 Examples include the anti-
inflammatory and analgesic drugs Indomethacin or Diclofenac
and the phytohormonal growth regulators indole-3-acetic acid
(IAA) or phenylacetic acid (PAA).2 Sterically demanding aryla-
cetic acids are also valuable intermediates forthe synthesis of modern
agrochemicals with insecticidal (e.g., Spiromesifen, Spirotetramat)
or herbicidal (e.g., Pinoxaden) activity (Figure 1).3 Therefore,
efficient procedures for the introduction of the methylenecar-
boxyl group into functionalized molecules are of considerable
interest.4
Traditional syntheses of arylacetic acids involve multistep
synthesis, harsh reaction conditions that are incompatible with
sensitive functionalities, or toxic reagents. Examples are the hydro-
lysis of benzyl cyanides,5 the transition-metal-catalyzed carbony-
lation of benzyl halides,6 and the electrocatalytic carboxylation of
benzyl halides.7 Modern alternatives include the α-arylation of
ester enolates,8 coupling of malonates9 or β-ketoesters10 with
aryl halides with in situ dealkoxycarbonylation or retro-Claisen
condensation, and cross-coupling of α-halocarboxylic esters or
amides with arylboronic acids.11
In the course of our research on highly potent insecticides and
herbicides derived from sterically demanding arylacetic acids, we
evaluated many of the synthetic strategies mentioned above.
Unfortunately, all of these methods led to much lower yields for
our target structures than for the sterically less demanding
derivatives reported in the literature. Moreover, the tolerance
of halide groups was essential as they are beneficial for the
biologic activity of many of the target molecules.3
If any of the arylacetic acid syntheses discussed above was to
fulfill these requirements, it would be the coupling of boronic
acids with α-halocarboxylates. The reaction conditions of the
initial protocol are very mild (3 mol % Pd(OAc), 9 mol %
We systematically studied various combinations of palladium
precursors, ligands, and bases for the reaction of ethyl bromoa-
cetate with 2,6-dimethylphenylboronic acid (Table 1). Using 1
mol % palladium acetate as the palladium source and potassium
phosphate as the base, predominantly protodeborylation was
observed for most ligands including tri(1-naphthyl)phosphine,
in situ generated NHC ligands, and bulky phosphines commonly
used in cross-coupling chemistry. Solely with tris-o-tolylpho-
sphine, the desired product was detected in encouraging yields
(entries 1À6).
The yield could be improved by increasing the reaction
temperature to 60 °C. At even higher temperatures, the catalyst
decomposed with formation of palladium black, which resulted
Received: July 19, 2011
Published: August 24, 2011
r
2011 American Chemical Society
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|

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NOTE
Figure 1. Examples of biologically active compounds derived from α-arylacetic acids.
Scheme 1. Cross-Coupling Reaction between Boronic Acids
and Ethyl Bromoacetate
next investigated whether it would be generally applicable also to
other substrates. As can be seen in Table 2, various arylboronic
acids were coupled with α-bromocarbonyl compounds, giving
the corresponding arylacetates in high yields using only 0.3 mol %
palladium (Table 2). The protocol is uniquely effective for
sterically demanding boronic acids 1aÀi. However, non-ortho-
substituted boronic acids also gave yields that are comparable to
those previously obtained using a 10-fold higher catalyst loading.
Both electron-withdrawing and electron-donating functional groups
were tolerated (3jÀo). We were especially pleased to see that
aromatic chloride groups did not give rise to any side reactions.
The presence of bromide substuients is also tolerated as can be
seen from the successful coupling of 4-bromobutyl bromoacetate
(2d). Besides alkyl bromoacetates, bromoacetamides (2b) and
even α-bromo ketones (2c), which gave no reaction with
previous palladium systems,11a,b,d can be employed as coupling
partners (3pÀq).
in a drop of activity and the formation of o-xylene as the major
product (entries 7, 8). The choice of the palladium source also
had a pronounced influence on the activity. Clearly better results
were obtained with Pd(dba)2 (entries 7 vs 10, 11). Further
improvements of yield and selectivity were achieved when using
the inexpensive ethyl bromoacetate in excess rather than the
costly boronic acid (entry 11).
We next varied the base and found that for this combination
of substrates, KF was more effective than K2CO3 or K3PO4
(entries 11À13). In contrast, phosphate bases were reported to give
best results for sterically less demanding boronic acids.11 The
addition of small quantities of water, which had been beneficial in
the previous protocols,11a,d led to increased conversion but also to a
lower selectivity with regard to protodeborylation (entry 14).
The decisive progress was made by adding phase-transfer
catalysts to increase the concentration of fluoride ions in solution
and thus facilitate the transmetalation step. The presence of 10
mol % of quaternary ammonium salts sharply improved yields
and selectivities (entries 15À18). Benzyltriethylammonium bro-
mide was found to be particularly advantageous in that it has a
comparatively low hygroscopicity and can easily be handled even
in small quantities. In the presence of this phase-transfer catalyst,
the desired product was obtained in 93% yield along with only
7% of the protodeborylation product 4a (entry 18).
In conclusion, the use of tetraalkylammonium salts as phase-
transfer reagents together with potassium fluoride as the base
allows coupling of various arylboronic acids with α-bromocar-
bonyl compounds in the presence of only 0.3 mol % of a catalyst
generated in situ from Pd(dba)2 and tri-o-tolylphosphine. The
yields obtained with the new catalyst system, which exclusively
comprises commercially available components, are comparable
to the best ones previously obtained using at least 10-fold higher
catalyst loadings. The new protocol is particularly effective for the
synthesis of sterically demanding arylacetic esters, key inter-
mediates en route to a new class of potent insecticides and
herbicides.
’ EXPERIMENTAL SECTION
General Procedure for the Synthesis of Arylacetic Acid
Derivatives. An oven-dried 20 mL flask was charged with the boronic
acid 1aÀo (1.00 mmol), Pd(dba)2 (1.73 mg, 3.00 μmol), tri(o-tolyl)-
phosphine (2.74 mg, 9.00 μmol), benzyltriethylammonium bromide
(27.8 mg, 0.10 mmol) and potassium fluoride (174 mg, 3.00 mmol). The
reaction flask was closed, evacuated, and flushed with nitrogen. Subse-
quently, ethyl bromoacetate (2a) (167 mg, 1.50 mmol), the internal
standard n-tetradecane (50 μL), and dry degassed THF (2 mL) were
added via syringe. The resulting mixture was stirred at 60 °C for 24 h,
diluted with ethyl acetate, and filtered through a pad of Celite and basic
alumina (2:1). The filter cake was rinsed with ethyl acetate (20 mL).
To permit the use of the reaction in an industrial synthesis, a
further reduction of catalyst loading was imperative. We were
thus delighted to find that in combination with benzyltriethy-
lammonium bromide 0.3 mol % palladium is sufficient to ensure
high yields. Even at 0.1 mol % catalyst loading, reasonable yields
were obtained (entries 19À21).
Having thus found a simple but highly effective catalyst system
for the coupling of sterically demanding arylboronic acids, we
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NOTE
Table 1. Development of the Catalyst Systema
no.
Pd
ligand
3% PPh3
base
additive
T (°C)
3a (%)
4a (%)
1
1% Pd(OAc)2
1% Pd(OAc)2
1% Pd(OAc)2
1% Pd(OAc)2
1% Pd(OAc)2
1% Pd(OAc)2
1% Pd(OAc)2
1% Pd(OAc)2
1% Pd(acac)2
1% Pd(dba)2
1% Pd(dba)2
1% Pd(dba)2
1% Pd(dba)2
1% Pd(dba)2
1% Pd(dba)2
1% Pd(dba)2
1% Pd(dba)2
1% Pd(dba)2
0.5% Pd(dba)2
0.3 Pd(dba)2
0.1 Pd(dba)2
5 equiv K3PO4
5 equiv K3PO4
5 equiv K3PO4
5 equiv K3PO4
5 equiv K3PO4
5 equiv K3PO4
5 equiv K3PO4
5 equiv K3PO4
5 equiv K3PO4
5 equiv K3PO4
5 equiv K3PO4
5 equiv K2CO3
5 equiv KF
20
20
20
20
20
20
60
80
60
60
60
60
60
60
60
60
60
60
60
60
60
0
0
26
23
48
18
35
20
30
34
13
30
13
12
8
2
3% PCy3
3
3% IMes HCl
0
3
4
3% IPr HCl
4
3
5
3% JohnPhos
3% P(o-Tol)3
3% P(o-Tol)3
3% P(o-Tol)3
3% P(o-Tol)3
3% P(o-Tol)3
3% P(o-Tol)3
3% P(o-Tol)3
3% P(o-Tol)3
3% P(o-Tol)3
3% P(o-Tol)3
3% P(o-Tol)3
3% P(o-Tol)3
3% P(o-Tol)3
1.5% P(o-Tol)3
0.9% P(o-Tol)3
0.3% P(o-Tol)3
5
6
12
29
18
5
7
8
9
10
11b
12b
13b
14b
15b
16b
17b
18b
19b
20b
21b
41
48
47
53
86
95
92
94
93
82
79
45
5 equiv KF
1 equiv H2O
14
5
3 equiv KF
TBAF 3H2O
3
3 equiv KF
TBACl
8
3 equiv KF
Aliquat 336
6
3 equiv KF
(PhCH2)N+(Et)3BrÀ
(PhCH2)N+(Et)3BrÀ
(PhCH2)N+(Et)3BrÀ
(PhCH2)N+(Et)3BrÀ
7
3 equiv KF
8
3 equiv KF
10
15
3 equiv KF
a Reaction conditions: 1.10 mmol 1a, 1.00 mmol 2a, Pd-source, phosphine ligand, base, 0.10 mmol additive, 2 mL THF, 24 h. dba = dibenzylidenacetone,
IMes HCl = 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride, IPr HCl = 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride. Yields were
3
3
determined by GC analysis, with n-tetradecane as internal standard. b 1.00 mmol 1a, 1.50 mmol 2a.
The filtrate was dried over MgSO4 and filtered, and the volatiles were
removed in vacuo. The residue was purified by column chromatography
yielding the corresponding arylacetic acid derivative.
Ethyl 2-o-Tolylacetate (3c) [CAS: 40291-39-2]. Compound 3c
was prepared following the general procedure starting from 2-methyl-
phenylboronic acid (136 mg, 1.00 mmol) and ethyl bromoacetate
(167 mg, 1.50 mmol). After column chromatography (SiO2, hexane/
ethyl acetate 5:1), 3c was isolated as a colorless liquid (99 mg, 56%). 1H
NMR (200 MHz, CDCl3) δ 7.18 (s, 4H), 4.10À4.22 (m, 2H), 3.63
(s, 2H), 2.33 (s, 3H), 1.21À1.31 (m, 3H) ppm; 13C NMR (50 MHz,
CDCl3) δ 171.9, 137.3, 133.4, 130.7, 130.6, 127.8, 126.5, 61.2, 39.7, 20.0,
14.6 ppm; MS (70 eV), m/z (%) 178 (15) [M+], 132 (15), 105 (100), 78
(11), 51 (7); IR (NaCl) υ~ 2980 (s), 1735 (s), 1155 (m), 1031 (m),
Ethyl 2-(2,6-Dimethylphenyl)acetate (3a) [CAS: 105337-15-3].
Compound 3a was synthesized following the general procedure
starting from 2,6-dimethylphenylboronic acid (150 mg, 1.00 mmol)
and ethyl bromoacetate (167 mg, 1.50 mmol). After column chro-
matography (SiO2, hexane/ethyl acetate 5:1), 3a was isolated as a
colorless liquid (157 mg, 82%). 1H NMR (400 MHz, CDCl3) δ
7.04À7.12 (m, 3H), 4.14À4.20 (m, 2H), 3.71 (s, 2H), 2.36 (s, 6H),
1.24À1.30 (m, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ 170.8,
136.9, 131.6, 127.8, 126.7, 60.3, 35.2, 19.9, 13.9 ppm; MS (70 eV),
m/z (%) 192 (21) [M+], 146 (13), 119 (100), 91 (26), 77 (10); IR
(NaCl) υ~ 2981 (w), 1712 (s), 16.38 (m), 1311 (m), 1202 (m), 1176
(m) cmÀ1. Anal. Calcd for C12H16O2: C 74.97; H 8.39. Found: C
74.84; H 8.29.
746 (m) cmÀ1
.
Ethyl 2-(2-Ethylphenyl)acetate (3d) [CAS: 105337-78-8].
Compound 3d was prepared following the general procedure starting
from 2-ethylphenylboronic acid (150 mg, 1.00 mmol) and ethyl bromo-
acetate (167 mg, 1.50 mmol). After column chromatography (SiO2,
hexane/ethyl acetate 5:1), 3d was isolated as a colorless liquid (127 mg,
61%). 1H NMR (200 MHz, CDCl3) δ 7.17À7.32 (m, 4H), 4.15À4.28
(m, 2H), 3.71 (s, 2H), 2.73 (q, J = 7.6 Hz, 2H), 1.24À1.36 (m, 6H) ppm;
13C NMR (50 MHz, CDCl3) δ 172.2, 143.0, 132.6, 130.8, 129.0, 127.9,
126.4, 61.2, 39.1, 26.2, 15.3, 14.6 ppm; MS (70 eV), m/z (%) 192 (9)
[M+],146 (36), 119 (100), 103 (14), 91 (42); IR (NaCl) υ~ 2968 (m),
Ethyl 2-Phenylacetate (3b) [CAS: 101-97-3]. Compound 3b
was prepared following the general procedure starting from phenyl-
boronic acid (122 mg, 1.00 mmol) and ethyl bromoacetate (167 mg,
1.50 mmol). After column chromatography (SiO2, hexane/ethyl acetate
5:1), 3b was isolated as a colorless liquid (121 mg, 74%). 1H NMR (400
MHz, CDCl3) δ 7.28À7.39 (m, 5H), 4.15À4.22 (m, 2H), 3.65 (s, 2H),
1.25À1.32 (m, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ 171.5, 134.3,
129.2, 128.5, 127.0, 60.8, 41.5, 14.2 ppm; MS (70 eV), m/z (%) 164 (12)
[M+], 136 (5), 91 (100), 65 (16), 40 (3); IR (NaCl) υ~ 2982 (w), 1736
2935 (w), 2875 (w), 1735 (s), 1153 (m), 1031 (m) cmÀ1
.
Ethyl 2-(2,4-Dimethylphenyl)acetate (3e) [CAS: 105337-16-4].
Compound 3e was prepared following the general procedure from 2,4-
dimethylphenylboronic acid (150 mg, 1.00 mmol) and ethyl bromoacetate
(167 mg, 1.50 mmol). After column chromatography (SiO2, hexane/ethyl
(s), 1254 (w), 1158 (m), 1030 (m) cmÀ1
.
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NOTE
Table 2. Synthesis of Arylacetic Acid Derivativesa
a Reaction conditions: 1.00 mmol 1aÀo, 1.50 mmol 2aÀd, 3.00 mmol KF, 0.3 mol % Pd(dba)2, 0.9 mol % P(o-Tol)3, 10 mol % (PhCH2)N+Et3BrÀ,
2 mL THF, 60 °C, 24 h. b 5.00 mmol KF, 1 mol % Pd(dba)2, 3 mol % P(o-Tol)3.
acetate 5:1), 3e was isolated as a colorless liquid (105 mg, 55%). 1H NMR
(200 MHz, CDCl3) δ 7.06À7.15 (m, 1H), 6.95À7.04 (m, 2H), 4.10À4.23
(m,2H),3.60(s,2H),2.31(d,J= 3.2 Hz, 6H), 1.21À1.32 (m, 3H) ppm; 13C
NMR (50 MHz, CDCl3) δ 172.1, 137.3, 137.0, 131.6, 130.5, 130.3, 127.2,
61.1, 39.3, 21.4, 19.9, 14.6 ppm; MS (70 eV), m/z (%) 192 (27) [M+], 146
(6), 119(100), 91(15), 65(3);IR(NaCl) υ~ 2980 (m), 2923(m), 1735(s),
1154 (s), 1032 (m) cmÀ1. Anal. Calcd for C12H16O2: C 74.97; H 8.39.
Found: C 75.24, H 8.40.
bromoacetate (167 mg, 1.50 mmol). After column chromatography
(SiO2, hexane/ethyl acetate 5:1), 3f was isolated as a colorless oil; 1H
NMR (400 MHz, CDCl3) δ 6.91 (s, 2H), 4.16 (q, J = 7.2 Hz, 2H), 3.71
(s, 2H), 2.61À2.69 (m, 4H), 2.32 (s, 3H), 1.19À1.28 (m, 9H) ppm; 13C
NMR (101 MHz, CDCl3) δ 171.9, 143.0, 136.7, 127.2, 127.1, 60.6, 34.0,
26.4, 21.1, 15.1, 14.2 ppm; HRMS (EI-TOF) calcd for C15H22O2,
234.1620, found 234.1635; MS (70 eV), m/z (%) 234 (37) [M+], 161
(100), 147 (33), 133 (40), 119 (13); IR (NaCl) υ~ 2966 (s), 1739 (s),
Ethyl 2-Mesitylacetate (3f) [CAS: 5460-08-2]. Compound 3f
was synthesized following the general procedure from 2,4,6-trimethyl-
phenylboronic acid (164 mg, 1.00 mmol) and ethyl bromoacetate
(167 mg, 1.50 mmol). After column chromatography (SiO2, hexane/
ethyl acetate 5:1), 3f was isolated as a colorless liquid (127 mg, 62%).
1H NMR (200 MHz, CDCl3) δ 6.89 (s, 2H), 4.10À4.25 (m, 2H), 3.67
(s, 2H), 2.27À2.37 (m, 9H), 1.27 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (50
MHz, CDCl3) δ 171.9, 137.4, 136.8, 129.3, 129.2, 61.1, 35.6, 21.3, 20.6,
14.7 ppm; MS (70 eV), m/z (%) 206 (23) [M+], 160, (7), 133 (100),
105 (10) 91 (11); IR (NaCl) υ~ 2978 (m), 2867 (w), 1732 (s), 1157 (m),
1458 (w), 1156 (m), 1032 (m) cmÀ1
.
Ethyl 2-(4-Chloro-2,6-dimethylphenyl)acetate (3h). Com-
pound 3h was prepared according to the general protocol starting from
4-chloro-2,6-dimethylphenylboronic acid (186 mg, 1.00 mmol) and
ethyl bromoacetate (167 mg, 1.50 mmol). After column chromatogra-
phy (SiO2, hexane/ethyl acetate 5:1), 3f was isolated as a colorless oil
that crystallized upon cooling; 1H NMR (400 MHz, CDCl3) δ 7.02 (s,
2H), 4.13 (q, J = 7.2 Hz, 2H), 3.62 (s, 2H), 2.29 (s, 6H), 1.23 (t, J = 7.2
Hz, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ 170.7, 139.0, 132.3,
130.3, 127.9, 60.8, 35.0, 20.1, 14.2 ppm; HRMS (EI-TOF) calcd for
C12H15O235Cl, 226.0761, found 226.0771; MS (70 eV), m/z (%) 226
(22) [M+], 180 (9), 153 (100), 115 (17), 91 (11); IR (NaCl) υ~ 2980
(m), 1733 (s), 1328 (w), 1155 (m), 1030 (m) cmÀ1; mp 26À27 °C.
1031 (m) cmÀ1
.
Ethyl 2-(2,6-Diethyl-4-methylphenyl)acetate (3g). Com-
pound 3g was synthesized following the general protocol starting from
2,6-diethyl-4-methylphenylboronic acid (186 mg, 1.00 mmol) and ethyl
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NOTE
Anal. Calcd for C12H15ClO2: C, 63.58; H, 6.67. Found: C, 63.30;
H, 6.78.
1.00 mmol) and ethyl bromoacetate (167 mg, 1.50 mmol). After column
chromatography (SiO2, hexane/ethyl acetate 5:1), 3n was isolated as a
yellow liquid (168 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J =
8.2 Hz, 2H), 7.34 (d, J = 8.5 Hz, 1H), 4.36 (q, J = 8.2 Hz, 2H), 4.15 (q, J =
8.2 Hz, 2H), 3.65 (s, 2H), 1.38 (t, J = 7.2 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H)
ppm; 13C NMR (151 MHz, CDCl3) δ 170.9, 166.4, 139.1, 129.8, 129.4,
129.3, 61.1, 60.9, 41.4, 14.3, 14.1 ppm; MS (70 eV), m/z (%) 237 (6)
[M+], 191 (39), 163 (100), 135 (39), 118 (13); IR (NaCl) υ~ 2982 (m),
2938 (w), 1735 (s), 1718 (s) 1277 (s) cmÀ1. Anal. Calcd for C13H16O4:
C 66.09; H 6.83. Found: C 65.98; H 7.05.
Ethyl 2-(4-Methoxyphenyl)acetate (3o) [CAS: 14062-18-1].
Compound 3o was prepared according to the general procedure from
4-methoxyphenylboronic acid (152 mg, 1.00 mmol) and ethyl bromoace-
tate (167 mg, 1.50 mmol). After column chromatography (SiO2, hexane/
ethyl acetate 5:1), 3o was isolated as a colorless liquid (155 mg, 77%). 1H
NMR (200 MHz, CDCl3) δ 7.25 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 8.7 Hz,
2H), 4.13À4.26 (m, 2H), 3.82 (s, 3H), 3.59 (s, 2H), 1.24À1.26 (m, 3H)
ppm; 13CNMR(50 MHz, CDCl3) δ172.3, 159.1, 130.7, 126.7, 114.4, 61.1,
55.6, 40.9, 14.6 ppm; MS (70 eV), m/z (%) 194 (24) [M+], 121 (100), 91
(8), 77 (10), 51 (4); IR (NaCl) υ~ 2981 (m), 2836 (w), 1732 (s), 1513 (s),
1247 (m), 1032 (m) cmÀ1. Anal. Calcd for C11H14O3: C 68.02; H 7.27.
Found: C 67.91; H 7.18.
Synthesis of 2-(2,6-Dimethylphenyl)-1-phenylethanone
(3p) [CAS: 23592-90-7]. Compound 3p was prepared following
the general procedure starting from 2,6-dimethylphenylboronic acid
(150 mg, 1.00 mmol), 2-bromo-1-phenylethanone (299 mg, 1.50 mmol),
Pd(dba)2 (5.75 mg, 0.01 mmol), tri-o-tolylphosphine (10.0 mg, 0.03
mmol), benzyltriethylammonium bromide (27.8 mg, 0.10 mmol) and
potassium fluoride (174 mg, 3.00 mmol). After column chromatography
(SiO2, hexane/ethyl acetate 5:1), 3i was isolated as a light yellow solid
(106 mg, 47%). 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.2 Hz, 2H),
7.66 (d, J = 7.4 Hz, 1H), 7.54À7.61 (m, 2H), 7.12À7.21 (m, 3H), 4.45
(s, 2H), 2.30 (s, 6H) ppm; 13C NMR (101 MHz, CDCl3) δ 196.9, 137.4,
137.0, 133.1, 132.5, 128.7, 128.1, 128.0, 126.9, 39.7, 20.4 ppm; MS
(70 eV), m/z (%) 223 (100) [M+], 131 (3), 105 (49), 103 (38), 77 (47);
IR (KBr) υ~ 1675 (s), 1654 (m), 1560 (w), 1449 (w), 1219 (s) cmÀ1; mp
110 °C. Anal. Calcd for C16H16O: C 85.68; H 7.19. Found: C 85.39;
H 7.22.
Ethyl 2-(Naphthalen-1-yl)acetate (3i) [CAS: 2122-70-5].
Compound 3i was prepared following the general procedure starting
from 1-naphthalinboronic acid (172 mg, 1.00 mmol) and ethyl bromoa-
cetate (167 mg, 1.50 mmol). After column chromatography (SiO2,
hexane/ethyl acetate 5:1), 3i was isolated as a colorless liquid (166 mg,
77%). 1H NMR (600 MHz, CDCl3) δ 8.04 (d, J = 8.3 Hz, 1H), 7.89 (d, J
= 8.1 Hz, 1H), 7.80À7.84 (m, 1H), 7.55À7.58 (m, 1H), 7.50À7.54
(m, 1H), 7.43À7.47 (m, 2H), 4.16À4.20 (m, 2H), 4.09 (s, 2H),
1.23À1.27 (m, 3H) ppm; 13C NMR (151 MHz, CDCl3) δ 171.7,
133.9, 132.2, 130.8, 128.8, 128.1, 128.0, 126.4, 125.8, 125.6, 123.9, 61.0,
39.4, 14.3 ppm; MS (70 eV), m/z (%) 214 (100) [M+], 141 (34), 115
(45), 89 (9), 63 (6); IR (NaCl) υ~ 3047 (w), 2981 (m), 1733 (s), 1173
(m), 1029 (m) cmÀ1. Anal. Calcd for C14H14O2: C 78.48; H 6.59.
Found: C 78.35; H 6.86.
Ethyl 2-p-Tolylacetate (3j) [CAS: 2122-70-5]. Compound 3j
was prepared according to the general procedure from 4-methylphe-
nylboronic acid (136 mg, 1.00 mmol) and ethyl bromoacetate (167 mg,
1.50 mmol). After column chromatography (SiO2, hexane/ethyl acetate
5:1), 3j was isolated as a colorless liquid (124 mg, 69%). 1H NMR (200
MHz, CDCl3) δ 7.10À7.22 (m, 4H), 4.09À4.22 (m, 2H), 3.58 (s, 2H),
2.34 (s, 3H), 1.21À1.32 (m, 3H) ppm; 13C NMR (50 MHz, CDCl3)
δ 172.2, 137.0, 131.6, 129.7, 129.5, 61.2, 41.5, 21.5, 14.6, ppm; MS
(70 eV), m/z (%) 178 (24) [M+], 105 (100), 77 (14), 91 (3), 50 (4); IR
(NaCl) υ~ 2981 (m), 2926 (w), 1736 (s), 1515 (m), 1153 (m), 1032
(m) cmÀ1
.
Ethyl 2-(4-Fluorophenyl)acetate (3k) [CAS: 587-88-2].
Compound 3k was prepared according to the general procedure from
4-fluorphenylboronic acid (140 mg, 1.00 mmol) and ethyl bromoacetate
(167 mg, 1.50 mmol). After column chromatography (SiO2, hexane/
ethyl acetate 5:1), 3k was isolated as a colorless liquid (60 mg, 33%).
1H NMR (600 MHz, CDCl3) δ 7.25À7.29 (m, 2H), 7.01À7.06
(m, 2H), 4.15À4.20 (m, 2H), 3.61 (s, 2H), 1.28 (t, J = 7.2 Hz, 3H)
ppm; 13C NMR (151 MHz, CDCl3) δ 171.5, 162.8, 161.2, 130.0, 130.8,
129.9, 115.5, 115.4, 61.0, 40.6, 14.2 ppm; MS (70 eV), m/z (%) 182 (17)
[M+], 109 (100), 83 (15), 57 (5), 40 (2); IR (NaCl) υ~ 2984 (m), 1736
(s), 1510 (s), 1155 (m), 1031 (m) cmÀ1
.
2-(2,6-Dimethylphenyl)-1-(piperidin-1-yl)ethanone (3q).
Compound 3q was prepared following the general procedure starting from
2,6-dimethylphenylboronic acid (150 mg, 1.00 mmol), N-(bromoa-
cetyl)piperidine12 (309 mg, 1.50 mmol), Pd(dba)2 (5.75 mg, 0.01 mmol),
tri-o-tolyphosphine (9.13 mg, 0.03 mmol) and potassium fluoride (290
mg, 5.00 mmol). After column chromatography (SiO2, hexane/ethyl
acetate 2:3), 3q was isolated as a colorless solid. 1H NMR (600 MHz,
CDCl3) δ 7.01À7.07 (m, 3H), 3.66 (s, 2H), 3.59 (s, 2H), 3.54 (s, 2H),
2.26(s, 6H), 1.67 (d, J = 5.3 Hz, 2H), 1.54À1.62 (m, 4H) ppm; 13C
NMR (151 MHz, CDCl3) δ 168.5, 136.9, 133.5, 128.0, 126.6, 46.8, 43.2,
34.0, 26.7, 25.8, 24.7, 20.4 ppm; HRMS (EI-TOF) calcd for C15H21NO,
231.1623, found 231.1607; MS (70 eV), m/z (%) 231 (48) [M+], 217
(16), 119 (24), 112 (100), 84 (14), 69 (60); IR (KBr) υ~ 2935 (m), 2854
(w), 1636 (s), 1443 (m), 1219 (m), 771 (w) cmÀ1; mp 72À73 °C.
4-Bromobutyl 2-(2,6-Dimethylphenyl)acetate (3r). Com-
pound 3r was synthesized following the general procedure starting from
2,6-dimethylphenylboronic acid (150 mg, 1.00 mmol) and 4-bromobu-
tyl bromoacetate13 (411 mg, 1.50 mmol). After column chromatography
(SiO2, hexane/ethyl acetate 5:1), 3r was isolated as a colorless liquid
Ethyl 2-(4-Chlorophenyl)acetate (3l) [CAS: 14062-24-9].
Compound 3l was synthesized following the general procedure from
4-chlorophenylboronic acid (156 mg, 1.00 mmol) and ethyl bromoace-
tate (167 mg, 1.50 mmol). After column chromatography (SiO2,
hexane/ethyl acetate 5:1), 3l was isolated as a colorless liquid (114
mg, 57%). 1H NMR (600 MHz, CDCl3) δ 7.30À7.33 (m, 2H), 7.23À
7.26 (m, 2H), 4.15À4.19 (m, 2H), 3.60 (s, 2H), 1.25À1.29 (m, 3H)
ppm; 13C NMR (151 MHz, CDCl3) δ 171.2, 133.0, 132.6, 130.7, 129.2,
129.0, 128.7, 61.1, 40.7, 14.2 ppm; MS (70 eV), m/z (%) 198 (25) [M+],
125 (100), 89 (22), 73 (3), 63 (11); IR (NaCl) υ~ 2983 (m), 1735 (s),
1493 (s), 1158 (m), 1031 (m) cmÀ1
.
Ethyl 2-(4-Acetylphenyl)acetate (3m) [CAS: 1528-42-3].
Compound 3m was prepared according to the general procedure
starting from 4-acetylphenylboronic (164 mg, 1.00 mmol) and ethyl
bromoacetate (167 mg, 1.50 mmol). After column chromatography
(SiO2, hexane/ethyl acetate 5:1), 3i was isolated as a colorless solid (124
mg, 60%). 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.2 Hz, 2H), 7.37
(d, J = 8.5 Hz, 2H), 4.11À4.17 (m, 2H), 3.66 (s, 2H), 2.58 (s, 3H),
1.20À1.27 (m, 3H) ppm; 13C NMR (151 MHz, CDCl3) δ 197.7, 170.8,
139.5, 136.0, 129.6, 128.6, 61.1, 41.3, 26.6, 14.2 ppm; MS (70 eV), m/z
(%) 192 (100),164 (16), 134 (14), 105 (19), 89 (11); IR (KBr) υ~ 2981
(w), 1735 (s), 1682 (m), 1274 (m), 1178 (m) cmÀ1; mp 55À56 °C.
Anal. Calcd for C12H14O3: C 69.88; H 6.84. Found: C 69.95. H 6.99.
Synthesis of Ethyl 4-(2-Ethoxy-2-oxoethyl)benzoate (3n)
[CAS: 3516-89-0]. Compound 3n was prepared following the general
procedure starting from 4-ethoxycarbonylphenylboronic acid (194 mg,
1
(144 mg, 48%). H NMR (600 MHz, CDCl3) δ 7.02À7.06 (m, 3H),
4.11 (t, J = 6.2 Hz, 2H), 3.68 (s, 2H), 3.35 (t, J = 6.2 Hz, 2H), 2.32
(s, 6H), 1.86 (m, 2H), 1.76 (m, 2H) ppm; 13C NMR (101 MHz, CDCl3)
δ 171.3, 137.1, 131.6, 128.1, 127.1, 63.8, 35.4, 33, 29.2, 27.3, 20.3 ppm;
HRMS (EI-TOF) calcd for C14H19O280Br, 298.0568, found 298.0565;
MS (70 eV), m/z (%) 300(4) [82BrM+], 298 (5) [80Br M+], 137 (44),
135 (54), 119 (100), 118 (35), 117 (18), 91 (24), 55 (20); IR ATR
8111
dx.doi.org/10.1021/jo2014998 |J. Org. Chem. 2011, 76, 8107–8112

The Journal of Organic Chemistry
NOTE
υ~ 3021 (w), 2958 (w), 1729 (vs), 1590 (w), 1471 (w), 1444 (w), 1328
(10) (a) Zeevaart, J. G.; Parkinson, C. J.; de Koning, C. B. Tetra-
hedron Lett. 2004, 45, 4261–4264. (b) Zeevaart, J. G.; Parkinson, C. J.; de
Koning, C. B. Tetrahedron Lett. 2007, 48, 3289–3293.
(w), 1244 (m), 1147 (vs), 1096 (w), 1032 (w), 1006 (w), 956 (w), 768
(s), 694 (w), 677 (w), 650 (w) cmÀ1
.
(11) (a) Gooßen, L. J. Chem. Commun. 2001, 669–670. (b) Liu,
X.-X.; Deng, M.-Z. Chem. Commun. 2002, 622–623. (c) Liu, C.; He, C.;
Shi, W.; Chen, M.; Lei, A. Org. Lett. 2007, 9, 5601–5604. (d) Peng, Z.-Y.;
Wang, J.-P.; Cheng, J.; Xie, X.-M.; Zhang, Z. Tetrahedron 2010,
66, 8238–8241. (e) Lundin, P. M.; Fu, G. C. J. Am. Chem. Soc. 2010,
132, 11027–11029.
(12) Gorske, B. C.; Bastian, B. L.; Geske, G. D.; Blackwell, H. E.
J. Am. Chem. Soc. 2007, 129, 8928–8929.
(13) Schneider, D. F.; Viljoen, M. S. Synth. Commun. 2002, 32, 721–728.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra. This
S
b
material is available free of charge via the Internet at http://pubs.
acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: goossen@chemie.uni-kl.de.
’ ACKNOWLEDGMENT
We thank NanoKat and the DFG (SFB/TRR 88 3MET) for
financial support of this work and Umicore AG for generous
donations of chemicals.
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