Copper-catalyzed coupling of aryl iodides and tert-butyl keto esters: Efficient access to α-aryl ketones and α-arylacetic acid tert-butyl esters

Article abstract of DOI:10.1016/j.tet.2013.10.017

CuI/trans-4-hydroxy-l-proline catalyzed coupling of aryl iodides with tert-butyl keto esters proceeded smoothly at 40 °C in DMF, providing α-aryl ketones after acid-promoted deprotection and decarboxylation of tert-butyl ester group. While CuI/2-picolinic acid catalyzed coupling of aryl iodides with tert-butyl acetoacetate at 70 °C in dioxane delivered α-arylacetic acid tert-butyl esters upon spontaneous deacylation. A wide range of functional groups, such as acetyl, methoxy, nitrile, nitro, bromo, and chloro were compatible with the reaction conditions.

Full text of DOI:10.1016/j.tet.2013.10.017

Tetrahedron 70 (2014) 3327e3332
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Copper-catalyzed coupling of aryl iodides and tert-butyl
b-keto
esters: efficient access to
tert-butyl esters
a-aryl ketones and a-arylacetic acid
*
*
Duo Zhao, Yongwen Jiang , Dawei Ma
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Lu, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 August 2013
Received in revised form 2 October 2013
Accepted 7 October 2013
Available online 14 October 2013
CuI/trans-4-hydroxy-
L
-proline catalyzed coupling of aryl iodides with tert-butyl
-aryl ketones after acid-promoted deprotection and de-
carboxylation of tert-butyl ester group. While CuI/2-picolinic acid catalyzed coupling of aryl iodides with
tert-butyl acetoacetate at 70 ꢀC in dioxane delivered
-arylacetic acid tert-butyl esters upon spontaneous
b-keto esters proceeded
smoothly at 40 ꢀC in DMF, providing
a
a
deacylation. A wide range of functional groups, such as acetyl, methoxy, nitrile, nitro, bromo, and chloro
were compatible with the reaction conditions.
Keyword:
Coupling
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
obtained by copper-catalyzed coupling of aryl halides and ethyl
acetoacetate and spontaneous deacylation, while Lei and co-
A number of pharmaceutically important molecules have
ketone or -arylacetic acid moiety, which includes anti-
inflammatory drugs diclofenac, ibuprofen, and naproxen.1 In addi-
tion, -aryl ketones or -arylacetic acid derivatives have been
proven to be valuable synthetic intermediates in organic synthesis.
Consequently great attention has been directed to developing con-
venient methods for preparing these two classes of compounds.1e11
Recent studies have demonstrated that transition metal catalyzed
arylation of carbonyl compounds is a powerful approach for as-
a
-aryl
workers demonstrated that
a-aryl ketones could be elaborated via
a
arylation of
b
-diketones and subsequent deacylation.11
Although the achievements in this area are significant, some
problems are still remained for practical usages in organic syn-
thesis. For Pd-catalyzed direct arylation of ketones and Cu-
a
a
catalyzed arylation of
regioselectivity is problematic if unsymmetrical aliphatic ketones
or -diketones are used as the coupling partners. For copper-
catalyzed coupling of aryl halides and ethyl acetoacetate, the re-
sultant -arylacetic acid ethyl esters may probably be hydrolyzed
b-diketones and subsequent deacylation,
b
sembling
a-aryl ketones or
a-arylacetic acid derivatives. For exam-
a
ple, Buchwald and Hartwig have independently reported that direct
arylation of ketones2,3 and esters4,5 is possible under the assistance
of palladium catalysts and sterically hindered phosphines and bases.
under the coupling conditions to give the relevant acids as the side
products. To solve these problems, we attempted to use conve-
niently available tert-butyl b-keto esters as the coupling partners
Goo
aryl ketones could be obtained via a Pd-catalyzed coupling of bo-
ronic acids with
-bromocarbonyl compounds,6 while Lei group
b
en and co-workers found that
a
-arylacetic acid esters and
a
-
(Scheme 1). We envisioned that their coupling products 3 might
undergo acid-promoted deprotection and decarboxylation to afford
a
a-aryl ketones 4 regioselectively, or base-promoted deacylation to
discovered that the same transformation could be affected by Ni-
catalysts.7 Since both catalysts and ligands are relatively cheap and
the reaction operation is simple, copper-catalyzed coupling reaction
provides another attractive choice, although only activated methy-
give -arylacetic acid tert-butyl esters 5.
a
2. Results and discussion
lene compounds, such as 1,3-diketones, b-keto esters, cyanoace-
tates, and malonates can be used as the coupling partners.8
By tuning reaction conditions, Guo9 and Koning10 groups in-
2.1. Assembly of
aryl iodides with tert-butyl
a
-aryl ketones via Cu-catalyzed coupling of
b-keto esters and subsequent
deprotection and decarboxylation
dependently revealed that a-arylacetic acid esters could be directly
With the idea in mind, we conducted a coupling of 4-iodo-bi-
* Corresponding authors. E-mail addresses: jiangyw@sioc.ac.cn (Y. Jiang),
madw@sioc.ac.cn, madw@mail.sioc.ac.cn (D. Ma).
phenyl and tert-butyl acetoacetate under our previous reaction
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.017

3328
D. Zhao et al. / Tetrahedron 70 (2014) 3327e3332
N-methylglycine or 2-picolinic acid (entries 3e6), and catalyst to
CuTc, CuCl, and CuBr (entries 7e9), we realized that trace of water
ꢀ
in solvent may play a role for deacylation. Thus, we added 4 A
molecule sieve, and were pleased that 3a was isolated in 77% yield
(entry 10). Additionally, it was observed that reducing the catalytic
loading gave a decreased yield (entry 11), indicating that using
20 mol % CuI is necessary to ensure good coupling yields.
Table 2
Copper-catalyzed coupling of 4-iodobiphenyl and tert-butyl acetoacetate in DMFa
Scheme 1. Assembly of
a-aryl ketones and a-arylacetic acid esters via copper-
catalyzed coupling.
conditions (10 mol % CuI, 20 mol % trans-4-hydroxy-L-proline,
Cs2CO3, DMSO, 40 ꢀC)8d to prepare 3a, and then explored suitable
conditions for its acid-promoted deprotection and decarboxylation.
As indicated in Table 1, it was found that both solvent and acid play
a key role for our desired transformation. When 3a was treated
with TFA and HCl in DMSO at 90 ꢀC, 4a was isolated in moderate
yields (entries 1 and 2). Since the problem in these cases was in-
complete conversion, we decided to increase reaction tempera-
tures. Complete conversion was observed at 130 ꢀC, but
decomposition occurred dramatically, leading to formation of 4a in
only 9% yield (entry 3). When acid was changed to TsOH (entry 4),
incomplete conversion was still observed in DMSO, although in
toluene 4a was obtained in 92% yield (entry 5). Complete conver-
sion could also be reached by treatment of 3a with TFA in DCM at
room temperature (entry 6). However, both toluene and DCM are
not good solvents for CuI/amino acid-catalyzed coupling, and
therefore they were not considered in developing a one-pot pro-
cess. Finally, we found that combination of HCl and DMF could
provide 4a in 95% yield at 130 ꢀC.
Entry
[Cu]
Ligand
Temp (ꢀC)
Yieldb (%)
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuTc
CuCl
CuBr
CuI
A
A
B
C
D
E
A
A
A
A
A
40
55
40
40
40
40
40
40
40
40
40
67 (13)c
53 (24)c
42 (5)c
21 (0)c
29 (2)c
44 (2)c
44 (16)c
59 (15)c
59 (16)c
77 (2)c
48 (0)c
9
10d
11d,e
CuI
a
Reaction conditions: 4-iodobiphenyl (0.5 mmol), tert-butyl acetoacetate
(1.0 mmol), copper (I) salt (0.1 mmol), ligand (0.2 mmol), Cs2CO3 (2.0 mmol), DMF
(1 mL).
b
Isolated yield.
Yield for deacylation product 5a.
200 mg of 4 A molecule sieve were added.
CuI (0.05 mmol), ligand (0.1 mmol).
c
d
ꢀ
Table 1
e
Condition screening for deprotection and decarboxylation of 3a
On the basis of the above investigations, we attempted to de-
velop a one-pot process for the synthesis of
a-aryl ketones. As
demonstrated in Table 3, it was found that 4a was isolated in 69%
yield after direct treatment of the coupling reaction mixture with
HCl at 130 ꢀC (entry 1). This encouraging result prompted us to
check the reaction scope by varying aryl iodides and
To our delight, both electron-rich and electron-deficient aryl io-
dides worked well, providing the corresponding -aryl ketones
4beh in 61e80% yields (entries 2e8). Other -keto esters like ethyl,
n-propyl, iso-propyl, cyclohexanyl, 2-thiophenyl, and phenyl
substituted coupling partners were applicable, leading to formation
of 4iet in moderate to good yields (entries 9e20). Another notable
feature is that a wide range of functional groups, such as acetyl,
methoxy, nitrile, nitro, and chloro were compatible with the re-
b-keto esters.
Entry
Conditions
Yield (%)
a
1
2
3
4
5
6
7
CF3CO2H, DMSO, 90 ꢀC
Concd HCl, DMSO, 90 ꢀC
Concd HCl, DMSO, 130 ꢀC
TsOH, DMSO, 130 ꢀC
TsOH, toluene, reflux
CF3CO2H, DCM, rt
49
50
9
20
92
75
95
b
Concd HCl, DMF, 130 ꢀC
action conditions, and thereby allowing diverse synthesis of
ketones.
a-aryl
We then investigated the coupling reaction of 4-iodobiphenyl
and tert-butyl acetoacetate using DMF as the solvent, and the re-
sults were summarized in Table 2. It was discovered that CuI/trans-
2.2. Preparation of a-arylacetic acid tert-butyl esters via Cu-
4-hydroxy- -proline catalyzed coupling in DMF gave 3a in 67%
L
catalyzed coupling of aryl iodides and tert-butyl b-keto esters
yield, together with 13% of deacylation product 5a (entry 1). More
deacylation product was isolated when reaction was carried out at
a higher temperature (entry 2). After failed in improving the
and spontaneous deacylation
We next turned our attention to develop a one-pot process for
synthesizing of -arylacetic acid tert-butyl esters. As mentioned
result by changing ligand to
L-proline, N,N-dimethyl-glycine,
a

D. Zhao et al. / Tetrahedron 70 (2014) 3327e3332
3329
before, deacylation product 5a was isolated in 13% yield when 4-
iodobiphenyl was reacted with tert-butyl acetoacetate (Table 2,
entry 1). We initially tried to promote the deacylation by adding
some water, but found that the result was not improved greatly
(Table 4, entry 1). Considering that the present coupling required
higher catalyst loading, we tried other conditions to see if the
results could be improved. Interestingly, under Kwong’s coupling
conditions (5 mol % of CuI, 10 mol % of 2-picolinic acid in 1,4-
dioxane),8g 5a was isolated in 86% yield if the reaction was car-
ried out at 70 ꢀC (entry 2). It seemed that using 2-picolinic acid as
the ligand is essential for obtaining good results because de-
creased yields were observed in the absence of the ligand or
Table 3
Synthesis of a-aryl ketones via a copper-catalyzed coupling of aryl iodides and tert-
butyl b
-keto estersa
Entry
1
Product
Yieldb (%)
changing ligand to trans-4-hydroxy-L-proline, L-proline, N,N-
dimethylglycine, and N-methylglycine (entries 3e7). Noteworthy
is that switching the base from Cs2CO3 to K2CO3 and K3PO4 led to
no conversion and a decreased yield, respectively (entries 9 and
10). Based on these observations, we concluded that the best
combination is using 2-picolinic acid as the ligand and Cs2CO3 as
the base.
69
4a: Y = 4-Ph
2
3
4
5
6
7
8
4b: Y¼4-OMe
4c: Y¼3-Me
4d: Y¼4-COMe
4e: Y¼4-CN
4f: Y¼4-NO2
4g: Y¼4-Cl
61
61
80
72
76
72
70
Table 4
4h: Y¼4-F
Coupling reaction of 4-iodobiphenyl and tert-butyl acetoacetate under various
conditionsa
9
68
76
4i: Y = 4-Ph
4j: Y¼4-NO2
10
11
12
13
14
60c
56c
65d
55d
Entry
mol % of CuI
Ligand
Solvent
Temp (ꢀC)
Yieldb (%)
4k: Y = 4-CN
4l: Y¼3-Cl
1d
2
3
4
5
20
5
5
5
5
5
5
5
5
A
E
d
A
B
C
D
E
E
DMF
40
70
70
70
70
70
70
70
70
29(48)c
86
38
42
71
53
68
0
55
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-dioxane
1,4-Dioxane
1,4-Dioxane
6
4m: Y = 4-COMe
4n: Y¼3-Me, 5-Me
7
8e
9f
a
Reaction conditions: 4-iodobiphenyl (1.0 mmol), tert-butyl acetoacetate
(2.0 mmol), CuI, ligand (entry 1: 40 mol %; entries 2e9: 10 mol %), Cs2CO3 (3 mmol),
solvent (2 mL), 70 ꢀC, 48 h, under argon.
15
64d
b
Isolated yield.
c
Yield for direct coupling product 3a.
After the reaction mixture was stirred at 40 ꢀC for 24 h, 0.5 mL of H2O was added
d
4o: Y = 4-NO2
16
17
4p: Y¼4-COMe
71d
51d
and then the reaction mixture was stirred for 16 h.
e
4q: Y¼3-OMe
K2CO3 was used.
K3PO4 was used.
f
The established optimized conditions were then examined with
a series of substituted aryl iodides to check the reaction scope and
limitations. As illustrated in Table 5, all tested aryl iodides gave the
18
19
64c
63c
4r: Y = 4-COMe
corresponding a-arylacetic acid tert-butyl ester in good yields. It is
4s: Y¼4-NO2
notable that when 1-bromo-3-iodobenzene and 1-bromo-4-
iodobenzene were used, coupling reaction proceeded exclusively
at the aryl iodide part, and the remaining bromide functionality
could be further used for other coupling reactions to assemble more
complicated compounds (entries 6 and 7).
20
44d
4t: R = 4-COMe
a
Reaction conditions: aryl iodide (0.5 mmol), tert-butyl keto ester (1.0 mmol), CuI
3. Conclusions
ꢀ
(0.1 mmol), trans-4-hydroxy-L-proline (0.2 mmol), Cs2CO3 (2.0 mmol), 4 A MS
(200 mg), DMF (1 mL), 40 ꢀC, 24 h; then adding 12 N HCl (2 mL), 130 ꢀC, 20e25 min.
b
Isolated yield.
In summary, we have identified suitable reaction conditions for
c
Coupling reaction was carried out at 55 ꢀC.
selectively preparing
through a copper-catalyzed coupling of aryl iodides and tert-butyl
-keto esters. The highly functional group tolerance in these two
a-aryl ketones and a-arylacetic acid esters
d
Coupling reaction was carried out at 60 ꢀC.
b

3330
D. Zhao et al. / Tetrahedron 70 (2014) 3327e3332
127.18 (2C), 50.75, 29.52. EI-HRMS calcd for C15H14O (Mþ) requires
m/z 210.1045, found m/z 210.1048.
Table 5
Synthesis of
a-arylacetic acid tert-butyl ester via CuI/2-picolinic acid catalyzed
coupling of aryl iodides and tert-butyl acetoacetatea
4.2.2. 1-(4-Methoxyphenyl)propan-2-one (4b).12 Pale yellow oil;
50 mg, 61% yield; 1H NMR (400 MHz, CDCl3)
d
7.12 (d, J¼8.8 Hz, 2H),
6.87 (d, J¼8.8 Hz, 2H), 3.79 (s, 3H), 3.63 (s, 2H), 2.14 (s, 3H). 13C NMR
(100 MHz, CDCl3)
d 207.01, 158.80, 130.51 (2C), 126.40, 114.30 (2C),
55.38, 50.23, 29.22. EI-HRMS calcd for C10H12O2 (Mþ) requires m/z
164.0837, found m/z 164.0835.
Entry
Y
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
4-CN
5b
5c
5d
5e
5f
5g
5h
5i
88
94
92
91c
85
92
84
83
85
4.2.3. 1-m-Tolylpropan-2-one (4c). Pale yellow oil; 46 mg, 61%
4-CO2Me
4-COMe
4-OMe
4-Me
4-Br
3-Br
yield; 1H NMR (400 MHz, CDCl3)
d 7.21e7.26 (m, 1H), 7.08 (d,
J¼7.6 Hz, 1H), 7.00e7.02 (m, 2H), 3.65 (s, 2H), 2.34 (s, 3H), 2.15 (s,
3H). 13C NMR (100 MHz, CDCl3) 206.95, 138.58, 134.34, 130.27,
128.79, 127.97, 126.53, 51.15, 29.12, 21.29. EI-HRMS calcd for
C
10H12O (Mþ) requires m/z 148.0888, found m/z 148.0885.
3-F, 4-F
3-CF3
5j
4.2.4. 1-(4-Acetylphenyl)propan-2-one (4d).12 Pale yellow oil;
a
Reaction conditions: aryl iodide (1.0 mmol), tert-butyl acetoacetate (2.0 mmol),
CuI (0.05 mmol), 2-picolinic acid (0.1 mmol), Cs2CO3 (3.0 mmol), 1,4-dioxane (2 mL),
70 ꢀC, 33e48 h, under argon.
71 mg, 80% yield; 1H NMR (500 MHz, CDCl3)
d
7.93 (d, J¼8.0 Hz, 2H),
7.29 (d, J¼8.0 Hz, 2H), 3.77 (s, 2H), 2.59 (s, 3H), 2.19 (s, 3H). 13C NMR
b
Isolated yield.
The reaction was carried out at 80 ꢀC for 36 h.
(125 MHz, CDCl3)
d 205.11, 197.73, 139.52, 136.08, 129.72 (2C),
c
128.76 (2C), 50.67, 29.60, 26.59. EI-HRMS calcd for C11H12O2 (Mþ)
requires m/z 176.0837, found m/z 176.0840.
one-pot processes has enabled us to prepare a variety of
a-aryl
4.2.5. 4-(2-Oxopropyl)benzonitrile (4e).13 Pale yellow solid; 58 mg,
ketones and -arylacetic acid esters. These procedures may find
a
72% yield; mp 56e58 ꢀC. 1H NMR (400 MHz, CDCl3)
d 7.60 (d,
applications in organic synthesis.
J¼8.0 Hz, 2H), 7.29 (d, J¼8.4 Hz, 2H), 3.78 (s, 2H), 2.20 (s, 3H). 13
C
NMR (100 MHz, CDCl3)
d 204.52, 139.52, 132.42 (2C), 130.45 (2C),
118.79, 111.06, 50.42, 29.90. EI-HRMS calcd for C10H9NO (Mþ) re-
4. Experimental
quires m/z 159.0684, found m/z 159.0686.
4.1. General remarks
4.2.6. 1-(4-Nitrophenyl)propan-2-one (4f).11 Pale yellow oil; 68 mg,
76% yield; 1H NMR (400 MHz, CDCl3)
d
8.19 (d, J¼8.8 Hz, 2H), 7.35
All solvents were purified and dried prior to use. 1H NMR and
(d, J¼8.4 Hz, 2H), 3.85 (s, 2H), 2.24 (s, 3H). 13C NMR (100 MHz,
13C NMR spectra were recorded on a Bruker Avance 400 MHz and
500 MHz, and assigned in parts per million (
shifts were given on the scale (ppm) and were referenced to
d
). 1H NMR chemical
CDCl3) d 204.29,147.24,141.58,130.61 (2C),123.92 (2C), 50.19, 30.01.
EI-HRMS calcd for C9H9NO3 (Mþ) requires m/z 179.0582, found m/z
d
internal TMS. Reference peaks for chloroform in 13C NMR spectra
were set at 77.0 ppm. High-resolution mass spectra were recor-
ded on an IonSpec 4.7 Tesla FTMS instrument. Silica gel
plate GF254 were used for thin layer chromatography (TLC) and
silica gel H or 300e400 mesh were used for flash column
chromatography.
179.0580.
4.2.7. 1-(4-Chlorophenyl)propan-2-one (4g).12 Pale yellow oil;
61 mg, 72% yield; 1H NMR (400 MHz, CDCl3)
d
7.30 (d, J¼8.4 Hz, 2H),
7.13 (d, J¼8.8 Hz, 2H), 3.67 (s, 2H), 2.16 (s, 3H). 13C NMR (100 MHz,
CDCl3) d 205.81, 133.17, 132.71, 130.90 (2C), 128.98 (2C), 50.18, 29.81.
EI-HRMS calcd for C9H9ClO (Mþ) requires m/z 168.0342, found m/z
168.0341.
4.2. General procedure for the synthesis of a-aryl ketones
4.2.8. 1-(4-Fluorophenyl)propan-2-one (4h).11 Pale yellow oil;
A Schlenk tube was charged with aryl iodide (0.5 mmol), CuI
(19 mg, 0.1 mmol), trans-4-hydroxy- -proline (26 mg,
53 mg, 70% yield; 1H NMR (400 MHz, CDCl3)
d 7.14e7.17 (m, 2H),
L
7.20 (t, J¼8.4 Hz, 2H), 3.68 (s, 2H), 2.16 (s, 3H). 13C NMR (100 MHz,
ꢀ
0.2 mmol), cesium carbonate (652 mg, 2.0 mmol), and 4 A
molecule sieve (200 mg). The tube was evacuated and backfilled
with argon three times before tert-butyl b-keto ester (1.0 mmol)
CDCl3)
d
206.28, 162.11 (J¼251.5 Hz), 131.07 (2C, J¼8.1 Hz), 130.01
(J¼2.5 Hz), 115.73 (2C, J¼21 Hz), 50.06, 29.44. EI-HRMS calcd for
C9H9FO (Mþ) requires m/z 152.0637, found m/z 152.0639.
and 1 mL of dry DMF was added. Then the reaction mixture was
stirred at the indicated temperatures for 24 h. After 2 mL of
12 N HCl was added, the reaction mixture was heated at 130 ꢀC
for 20e25 min. The cooled mixture was partitioned between
ethyl acetate and saturated NH4Cl, the organic layer was washed
with brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
4.2.9. 1-(Biphenyl-4-yl)butan-2-one (4i). White solid; 76 mg, 68%
yield; mp 42e43 ꢀC. 1H NMR (400 MHz, CDCl3)
d 7.54e7.59 (m, 4H),
7.41e7.45 (m, 2H), 7.32e7.36 (m, 1H), 7.25e7.29 (m, 2H), 3.73 (s,
2H), 2.52 (q, J¼7.2 Hz, 2H), 1.05 (t, J¼7.2 Hz, 3H). 13C NMR
(100 MHz, CDCl3)
d 208.24, 140.90, 140.06, 133.62, 129.95 (2C),
128.91 (2C), 127.58 (2C), 127.42, 127.19 (2C), 49.52, 35.48, 7.94. EI-
HRMS calcd for C16H16O (Mþ) requires m/z 224.1201, found m/z
224.1204.
(eluting with PE/EA¼20:1 to 3:1) to provide the desired
a-aryl
ketones.
4.2.1. 1-(Biphenyl-4-yl)propan-2-one (4a).12 White solid, 73 mg,
69% yield; mp 58e59 ꢀC; 1H NMR (500 MHz, CDCl3)
7.58e7.60 (m,
4H), 7.44 (t, J¼8.0 Hz, 2H), 7.35 (t, J¼7.5 Hz, 1H), 7.28 (d, J¼8.0 Hz,
2H), 3.75 (s, 2H), 2.20 (s, 3H). 13C NMR (125 MHz, CDCl3)
206.44,
140.84, 140.18, 133.36, 129.96 (2C), 128.91 (2C), 127.62 (2C), 127.44,
4.2.10. 1-(4-Nitrophenyl)butan-2-one (4j). Pale yellow solid; 73 mg,
d
76% yield; mp 57e58 ꢀC. 1H NMR (400 MHz, CDCl3)
d 8.16 (d,
J¼8.8 Hz, 2H), 7.35 (d, J¼8.8 Hz, 2H), 3.82 (s, 2H), 2.54 (q, J¼7.2 Hz,
d
2H), 1.06 (t, J¼7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 207.04,
147.10, 141.87, 130.55 (2C), 123.80 (2C), 48.92, 36.13, 7.77. EI-HRMS

D. Zhao et al. / Tetrahedron 70 (2014) 3327e3332
3331
calcd for C10H11NO3 (Mþ) requires m/z 193.0739, found m/z
193.0738.
134.52, 132.84, 129.84 (2C), 128.80 (2C), 128.40, 46.19, 26.69. EI-
HRMS calcd for C14H12O2S (Mþ) requires m/z 244.0558, found m/z
244.0557.
4.2.11. 4-(2-Oxopentyl)benzonitrile (4k).14 Pale yellow solid; 56 mg,
60% yield; mp 53e55 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.60 (d,
4.2.19. 2-(4-Nitrophenyl)-1-(thiophen-2-yl)ethanone
solid, 78 mg, 63% yield; mp 127e128 ꢀC. 1H NMR (400 MHz,
CDCl3)
8.19 (d, J¼6.4 Hz, 2H), 7.81 (d, J¼3.2 Hz, 1H), 7.70 (d,
J¼3.2 Hz, 1H), 7.47 (d, J¼7.2 Hz, 2H), 7.17 (t, J¼3.2 Hz, 1H), 4.32 (s,
2H). 13C NMR (100 MHz, CDCl3)
188.81, 147.32, 143.46, 141.69,
(4s). White
J¼8.0 Hz, 2H), 7.29 (d, J¼8.0 Hz, 2H), 3.75 (s, 2H), 2.46 (t, J¼7.6 Hz,
2H), 1.57e1.62 (m, 2H), 0.88 (t, J¼7.2 Hz, 3H). 13C NMR (100 MHz,
d
CDCl3)
d 206.71, 139.73, 132.38 (2C), 130.43 (2C), 118.83, 110.98,
49.60, 44.66, 17.19, 13.66. EI-HRMS calcd for C12H13NO (Mþ) re-
d
quires m/z 187.0997, found m/z 187.1002.
134.93, 132.91, 130.67 (2C), 128.55, 123.95 (2C), 45.80. EI-HRMS
calcd for C12H9NO3S (Mþ) requires m/z 247.0303, found m/z
247.0307.
4.2.12. 1-(3-Chlorophenyl)pentan-2-one (4l). Pale yellow oil; 55 mg,
56% yield; 1H NMR (500 MHz, CDCl3)
d 7.24e7.26 (m, 2H), 7.20 (s,
1H), 7.09 (d, J¼6.0 Hz, 1H), 3.66 (s, 2H), 2.44 (t, J¼7.6 Hz, 2H),
4.2.20. 2-(4-Acetylphenyl)-1-phenylethanone (4t).15 Pale yellow
solid; 53 mg, 44% yield; mp 141e143 ꢀC. 1H NMR (400 MHz, CDCl3)
1.59e1.62 (m, 2H), 0.89 (t, J¼7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d
207.62, 136.32, 134.56, 129.99, 129.70, 127.76, 127.32, 49.58, 44.32,
d
8.01 (d, J¼7.6 Hz, 2H), 7.93 (d, J¼8.0 Hz, 2H), 7.58 (t, J¼7.2 Hz, 1H),
7.47 (t, J¼8.0 Hz, 2H), 7.36 (d, J¼8.0 Hz, 2H), 4.35 (s, 2H), 2.58 (s, 3H).
13C NMR (100 MHz, CDCl3)
197.85, 196.86, 140.15, 136.48, 135.97,
17.29, 13.77. EI-HRMS calcd for C11H13ClO (Mþ) requires m/z
196.0655, found m/z 196.0650.
d
133.58, 129.96 (2C), 128.88 (2C), 128.81 (2C), 128.64 (2C), 45.43,
26.69. EI-HRMS calcd for C16H14O2 (Mþ) requires m/z 238.0994,
found m/z 238.0991.
4.2.13. 1-(4-Acetylphenyl)-3-methylbutan-2-one (4m). Pale yellow
oil; 66 mg, 65% yield; 1H NMR (400 MHz, CDCl3)
d
7.92 (d, J¼8.0 Hz,
2H), 7.29 (d, J¼8.0 Hz, 2H), 3.81 (s, 2H), 2.67e2.78 (m, 1H), 2.59 (s,
3H), 1.13 (d, J¼6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3)
d 210.94,
197.80, 140.00, 135.90, 129.85 (2C), 128.70 (2C), 47.38, 40.74, 26.67,
18.32 (2C). EI-HRMS calcd for C13H16O2 (Mþ) requires m/z 204.1150,
found m/z 204.1144.
4.3. General procedure for the synthesis of a-arylacetic acid
tert-butyl esters
A Schlenk tube was charged with aryl iodide (1.0 mmol), CuI
(9.5 mg, 0.05 mmol), 2-picolinic acid (12 mg, 0.10 mmol), and ce-
sium carbonate (978 mg, 3.0 mmol). The tube was evacuated and
backfilled with argon three times before tert-butyl acetoacetate
(2.0 mmol) and 2 mL of 1,4-dioxane was added. The tube was im-
mersed in an oil bath, and the reaction mixture was stirred at the
indicated temperatures for 33e48 h. The cooled mixture was par-
titioned between ethyl acetate and saturated NH4Cl, the organic
layer was washed with brine, dried over Na2SO4, and concentrated
in vacuo. The residue was purified by column chromatography on
4.2.14. 1-(3,5-Dimethylphenyl)-3-methylbutan-2-one
(4n). Pale
6.89 (s,
yellow oil; 52 mg, 55% yield; 1H NMR (500 MHz, CDCl3)
d
1H), 6.81 (s, 2H), 3.67 (s, 2H), 2.62e2.78 (m, 1H), 2.29 (s, 6H), 1.10 (d,
J¼8.5 Hz, 6H). 13C NMR (100 MHz, CDCl3)
d 212.41, 138.25, 134.37,
128.65 (2C), 127.37 (2C), 47.75, 40.08, 21.37 (2C), 18.51 (2C). EI-
HRMS calcd for C13H18O (Mþ) requires m/z 190.1358, found m/z
190.1354.
4.2.15. 1-Cyclohexyl-2-(4-nitrophenyl)ethanone (4o). Pale yellow
solid; 79 mg, 64% yield; mp 80e82 ꢀC. 1H NMR (400 MHz, CDCl3)
silica gel (eluting with PE/EA¼20:1 to 3:1) to provide the desired
a-
d
8.17 (d, J¼8.4 Hz, 2H), 7.34 (d, J¼8.4 Hz, 2H), 3.85 (s, 2H), 2.40e2.50
(m, 1H), 1.78e1.89 (m, 4H), 1.67e1.70 (m, 1H), 1.24e1.40 (m, 5H). 13
NMR (100 MHz, CDCl3) 209.48, 147.08, 142.08, 130.63 (2C), 123.80
(2C), 51.06, 47.14, 28.59 (2C), 25.86, 25.67 (2C). EI-HRMS calcd for
14H17NO3 (Mþ) requires m/z 247.1208, found m/z 247.1206.
arylacetic acid tert-butyl esters.
C
d
4.3.1. tert-Butyl 2-(biphenyl-4-yl)acetate (5a).16 White solid;
231 mg, 86% yield; mp 46e47 ꢀC. 1H NMR (400 MHz, CDCl3)
C
d
7.43e7.47 (m, 4H), 7.28e7.32 (m, 2H), 7.18e7.24 (m, 3H), 3.45 (s,
2H), 1.36 (s, 9H). 13C NMR (100 MHz, CDCl3)
d
170.86, 140.87, 139.77,
4.2.16. 2-(4-Acetylphenyl)-1-cyclohexylethanone (4p). White solid,
87 mg, 71% yield; mp 76e77 ꢀC. 1H NMR (400 MHz, CDCl3)
7.91 (d,
133.75, 129.65 (2C), 128.75 (2C), 127.19 (2C), 127.04 (2C), 80.80,
42.19, 28.05 (3C). EI-HRMS calcd for C18H20O2 (Mþ) requires m/z
268.1463, found m/z 268.1465.
d
J¼8.4 Hz, 2H), 7.28 (d, J¼8.0 Hz, 2H), 3.79 (s, 2H), 2.59 (s, 3H),
2.2e2.48 (m, 1H), 1.76e1.86 (m, 4H), 1.65e1.68 (m, 1H), 1.18e1.41
(m, 5H). 13C NMR (100 MHz, CDCl3)
d
210.31, 197.94, 140.07, 135.91,
4.3.2. tert-Butyl 2-(4-cyanophenyl)acetate (5b).17 Pale yellow oil;
129.91 (2C), 128.74 (2C), 50.73, 47.68, 28.64 (2C), 26.73, 25.89, 25.70
(2C). EI-HRMS calcd for C16 H20O2 (Mþ) requires m/z 244.1463,
found m/z 244.1467.
191 mg, 88% yield; 1H NMR (400 MHz, CDCl3)
d
7.59 (d, J¼6.8 Hz,
2H), 7.37 (d, J¼6.8 Hz, 2H), 3.58 (s, 2H), 1.42 (s, 9H). 13C NMR
(100 MHz, CDCl3)
d 169.66, 140.16, 132.30 (2C), 130.21 (2C), 118.87,
110.97, 81.68, 42.65, 28.05 (3C). EI-HRMS calcd for C13H15NO2 (Mþ)
4.2.17. 1-Cyclohexyl-2-(3-methoxyphenyl)ethanone (4q). Pale yel-
requires m/z 217.1103, found m/z 217.1105.
low oil; 59 mg, 51% yield; 1H NMR (500 MHz, CDCl3)
d 7.1e7.24 (m,
1H), 6.77e6.80 (m, 2H), 6.73 (s, 1H), 3.80 (s, 3H), 3.69 (s, 2H),
2.43e2.48 (m, 1H), 1.75e1.83 (m, 4H), 1.64e1.66 (m, 1H), 1.20e1.39
4.3.3. Methyl 4-(2-tert-butoxy-2-oxoethyl)benzoate (5c).5c Pale
yellow oil; 235 mg, 94% yield; 1H NMR (400 MHz, CDCl3)
d
7.95 (d,
J¼8.0 Hz, 2H), 7.30 (d, J¼8.4 Hz, 2H), 3.85 (s, 3H), 3.54 (s, 2H),1.39 (s,
9H). 13C NMR (100 MHz, CDCl3)
170.06,166.86,139.93,129.73 (2C),
(m, 5H). 13C NMR (125 MHz, CDCl3)
d 211.48, 159.89, 136.05, 129.69,
121.97, 115.22, 112.47, 55.34, 50.19, 48.06, 28.72 (2C), 25.95, 25.75
(2C). EI-HRMS calcd for C15H20O2 (Mþ) requires m/z 232.1463,
found m/z 232.1467.
d
129.27 (2C), 128.79, 81.12, 51.98, 42.60, 27.94 (3C). EI-HRMS
calcd for C14H18O4 (Mþ) requires m/z 250.1205, found m/z 250.1201.
4.2.18. 2-(4-Acetylphenyl)-1-(thiophen-2-yl)ethanone (4r). White
solid, 78 mg, 64% yield; mp 132e134 ꢀC. 1H NMR (500 MHz, CDCl3)
4.3.4. tert-Butyl 2-(4-acetylphenyl)acetate (5d).18 White solid; mp
48e50 ꢀC, 215 mg, 92% yield; 1H NMR (400 MHz, CDCl3)
d
7.81 (d,
J¼8.0 Hz, 2H), 7.26 (d, J¼8.4 Hz, 2H), 3.49 (s, 2H), 2.47 (s, 3H), 1.40
(s, 9H). 13C NMR (100 MHz, CDCl3)
197.57, 169.97, 140.08, 135.75,
129.42 (2C), 128.46 (2C), 81.11, 42.46, 27.90 (3C), 26.47. EI-HRMS
d
7.91 (d, J¼6.8 Hz, 2H), 7.77 (d, J¼3.2 Hz, 1H), 7.65 (d, J¼4.0 Hz, 1H),
7.39 (d, J¼7.2 Hz, 2H), 7.13 (t, J¼3.6 Hz, 1H), 4.25 (s, 2H), 2.57 (s, 3H).
13C NMR (125 MHz, CDCl3)
197.79, 189.58, 143.68, 139.79, 136.05,
d
d

3332
D. Zhao et al. / Tetrahedron 70 (2014) 3327e3332
calcd for C14H18O3 (Mþ) requires m/z 234.1256, found m/z
234.1255.
123.89 (q, J¼3.4 Hz), 81.45, 42.43, 28.09 (3C). EI-HRMS calcd for
C
13H15F3O2 (Mþ) requires m/z 260.1024, found m/z 260.1020.
4.3.5. tert-Butyl 2-(4-methoxyphenyl)acetate (5e).5b Pale yellow oil;
202 mg, 91% yield; 1H NMR (400 MHz, CDCl3) 1H NMR (400 MHz,
d
Acknowledgements
CDCl3)
d
7.19 (d, J¼8.4 Hz, 2H), 6.85 (d, J¼8.4 Hz, 2H), 3.79 (s, 3H),
3.46 (s, 2H), 1.43 (s, 9H). 13C NMR (100 MHz, CDCl3)
d
171.28, 158.55,
The authors are grateful to Chinese Academy of Sciences and
Ministry of Science & Technology (Grant 2009CB940900) for their
financial support.
130.20 (2C), 126.82, 113.89 (2C), 80.60, 55.21, 41.70, 28.03 (3C). EI-
HRMS calcd for C13H18O3 (Mþ) requires m/z 222.1256, found m/z
222.1262.
References and notes
4.3.6. tert-Butyl 2-p-tolylacetate (5f).19 Pale yellow oil; 175 mg, 85%
yield; 1H NMR (400 MHz, CDCl3)
d
7.14 (d, J¼8.0 Hz, 2H), 7.10 (d,
1. (a) Lednicer, D.; Mitscher, L. A. In The Organic Chemistry of Drug Synthesis; John
Wiley: New York, NY, 1980; Vol. 2, p 62; (b) Giordano, C.; Castaldi, G.; Uggeri, F.
Angew. Chem., Int. Ed. Engl. 1984, 23, 413; (c) Alper, H.; Hamel, N. J. Am. Chem.
Soc. 1990, 112, 2803; (d) Harrington, P. J.; Lodewijk, E. Org. Process Res. Dev. 1997,
1, 72.
J¼8.0 Hz, 2H), 3.46 (s, 2H), 2.30 (s, 3H), 1.42 (s, 9H). 13C NMR
(100 MHz, CDCl3)
d 171.18, 136.38, 131.72, 129.20 (2C), 129.11 (2C),
80.65, 42.25, 28.09 (3C), 21.10. EI-HRMS calcd for C13H18O2 (Mþ)
requires m/z 206.1307, found m/z 206.1306.
2. (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108; (b) Fox, J. M.;
Ahman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.; Buchwald, S. L. J. Am. Chem.
ꢀ
Soc. 1998, 120, 1918; (c) Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc.
2000, 122, 1360.
3. (a) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382; (b) Kawatsura,
M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473; (c) Liao, X.; Weng, Z.; Hartwig,
J. F. J. Am. Chem. Soc. 2008, 130, 195.
4. (a) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7996; (b) Spiel-
vogel, D. J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 3500.
5. (a) Lee, S.; Beare, N. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 8410; (b) Hama,
T.; Hartwig, J. F. Org. Lett. 2008, 10, 1545; (c) Hama, T.; Hartwig, J. F. Org. Lett.
2008, 10, 1549.
4.3.7. tert-Butyl 2-(4-bromophenyl)acetate (5g). Pale yellow oil;
248 mg, 92% yield; 1H NMR (400 MHz, CDCl3)
d
7.42 (d, J¼8.4 Hz,
2H), 7.14 (d, J¼8.4 Hz, 2H), 3.47 (s, 2H), 1.43 (s, 9H). 13C NMR
(100 MHz, CDCl3)
d 170.39, 133.75, 131.60 (2C), 131.04 (2C), 121.01,
81.13, 42.05, 28.07 (3C). EI-HRMS calcd for C12H15BrO2 (Mþ) re-
quires m/z 270.0255, found m/z 270.0251.
4.3.8. tert-Butyl 2-(3-bromophenyl)acetate (5h). Pale yellow oil;
6. (a) Gooben, L. J. Chem. Commun. 2001, 669; (b) Zimmermann, B.; Dzik, W. I.;
Himmler, T.; Goossen, L. J. J. Org. Chem. 2011, 76, 8107.
227 mg, 84% yield; 1H NMR (400 MHz, CDCl3)
d 7.34 (s, 1H), 7.29 (d,
J¼6.8 Hz, 1H), 7.06e7.12 (m, 2H), 3.40 (s, 2H), 1.35 (s, 9H). 13C NMR
7. Liu, C.; He, C.; Shi, W.; Chen, M.; Lei, A. Org. Lett. 2007, 9, 5601.
8. (a) Okuro, K.; Furuune, M.; Miura, M. J. Org. Chem. 1993, 58, 4716; (b) Kwong, F.;
Buchwald, S. L. Org. Lett. 2002, 4, 3517; (c) Cristau, H. J.; Cellier, P. P.; Spindler, J.
F.; Taillefer, M. Chem.dEur. J. 2004, 10, 5607; (d) Xie, X.; Cai, G.; Ma, D. Org. Lett.
2005, 7, 4693; (e) Jiang, Y.; Wu, N.; Wu, H. Synlett 2005, 2731; (f) Xie, X.; Chen,
Y.; Ma, D. J. Am. Chem. Soc. 2006, 128, 16050; (g) Yip, S. F.; Zhou, Z.; Kwong, F. Y.
Org. Lett. 2007, 9, 3469; (h) Mino, T.; Yagishita, F.; Shibuya, M.; Kajiwara, K.;
Shindo, H.; Sakamoto, M.; Fujita, T. Synlett 2009, 2457; (i) Huang, Z.; Hartwig, J.
F. Angew. Chem., Int. Ed. 2012, 51, 1028; (j) Xie, S.; Qin, P.; Li, M.; Zhang, X.; Jiang,
Y.; Ma, D. Tetrahedron Lett. 2013, 54, 3889.
9. Deng, W.; Wang, Y.; Liu, L.; Guo, Q. Chin. Chem. Lett. 2006, 17, 595.
10. Zeevaart, J. G.; Parkinsona, C. J.; de Koning, C. B. Tetrahedron Lett. 2007, 48, 3289.
11. He, C.; Guo, S.; Huang, L.; Lei, A. J. Am. Chem. Soc. 2010, 132, 8273.
12. Ackermann, L.; Mehta, V. P. Chem.dEur. J. 2012, 18, 10230.
13. Hesp, K. D.; Lundgren, R. J.; Stradiotto, M. J. Am. Chem. Soc. 2011, 133, 5194.
14. Arisawa, M.; Kuwajima, M.; Toriyama, F.; Li, G.; Yamaguchi, M. Org. Lett. 2012,
14, 3804.
(100 MHz, CDCl3)
d 170.24, 136.93, 132.39, 130.07, 130.02, 127.99,
122.47, 81.23, 42.17, 28.09 (3C). EI-HRMS calcd for C12H15BrO2 (Mþ)
requires m/z 270.0255, found m/z 270.0251.
4.3.9. tert-Butyl 2-(3,4-difluorophenyl)acetate (5i). Pale yellow oil;
189 mg, 83% yield; 1H NMR (400 MHz, CDCl3)
d
7.05e7.12 (m, 2H),
6.96e6.97 (m, 1H), 3.47 (s, 2H), 1.43 (s, 9H). 13C NMR (100 MHz,
CDCl3)
d
170.28, 150.25 (dd, J1¼246.1 Hz, J1¼12.7 Hz), 149.62 (dd,
J1¼245.5 Hz, J1¼12.4 Hz), 131.67 (q, J¼1.8 Hz), 125.40 (q, J¼2.8 Hz),
118.33 (d, J¼17.3 Hz), 117.21 (d, J¼17.1 Hz), 81.42, 41.74, 28.09 (3C).
EI-HRMS calcd for C12H14F2O2 (Mþ) requires m/z 228.0962, found
m/z 228.0967.
15. Battace, A.; Feuerstein, M.; Lemhadri, M.; Zair, T.; Doucet, H.; Santelli, M. Eur. J.
Org. Chem. 2007, 3122.
16. Jørgensen, M.; Lee, S.; Liu, X.; Wolkowski, J. P.; Hartwig, J. F. J. Am. Chem. Soc.
4.3.10. tert-Butyl 2-(3-(trifluoromethyl)phenyl)acetate (5j). Pale
yellow oil; 221 mg, 85% yield; 1H NMR (400 MHz, CDCl3)
2002, 124, 12557.
d
7.50e7.54 (m, 2H), 7.40e7.46 (m, 2H), 3.58 (s, 2H), 1.44 (s, 9H). 13
C
17. Biscoe, M. R.; Buchwald, S. L. Org. Lett. 2009, 11, 1773.
€
18. Knor, S.; Modlinger, A.; Poethko, T.; Schottelius, M.; Wester, H.-J.; Kessler, H.
NMR (100 MHz, CDCl3)
(q, J¼31.4 Hz), 129.00, 126.22 (q, J¼4.4 Hz), 124.26 (q, J¼271.3 Hz),
d
170.25, 135.75, 132.83 (d, J¼1.5 Hz), 130.93
Chem.dEur. J. 2007, 13, 6082.
19. Song, B.; Rudolphi, F.; Himmler, T.; Gooben, L. J. Adv. Synth. Catal. 2011, 353, 1565.