N-Heterocyclic carbene-palladium(II)-1-methylimidazole complex catalyzed a-arylation of symmetric dialkyl ketones with aryl chlorides

Article abstract of DOI:10.1016/j.ica.2014.07.061

N-Heterocyclic carbene-palladium(II)-1-methylimidazole [NHC-Pd(II)-Im] complex 1 showed efficient catalytic activity toward α-arylation of symmetric dialkyl ketones under mild conditions. It was found that the ratio of aryl chlorides and ketones drastical

Full text of DOI:10.1016/j.ica.2014.07.061

Inorganica Chimica Acta 423 (2014) 106–108
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N-Heterocyclic carbene-palladium(II)-1-methylimidazole complex
catalyzed
a-arylation of symmetric dialkyl ketones with aryl chlorides
⇑
Zheng-Kang Xiao, Hui-Ying Yin, Jian-Mei Lu
College of Chemistry and Materials Engineering, Wenzhou University, Chashan University Town, Zhejiang Province 325035, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 June 2014
Received in revised form 30 July 2014
Accepted 30 July 2014
Available online 11 August 2014
N-Heterocyclic carbene-palladium(II)-1-methylimidazole [NHC-Pd(II)-Im] complex 1 showed efficient
catalytic activity toward
a-arylation of symmetric dialkyl ketones under mild conditions. It was found
that the ratio of aryl chlorides and ketones drastically affected the reaction. When the ratio of aryl chlo-
rides and ketones was 1:2, mono-arylated products can be obtained in good to high yields as the sole;
while that of aryl chlorides and ketones was changed to 1:0.7, di- and mono-arylated products were
obtained in good to high total yields at the same time, with the former as the major.
Ó 2014 Elsevier B.V. All rights reserved.
Keywords:
N-Heterocyclic carbene-palladium complex
a-Arylation
Symmetric dialkyl ketone
Aryl chloride
Synthetic method
1. Introduction
the phosphine ligands are not readily available. In the NHC-metal
complexes catalyzed
a-arylation reactions of ketones reported,
Owing to the original contributions from Miura [1], Buchwald
only fewer examples on symmetric dialkyl ketones were involved,
implying their limitations on the substrate generality. For example,
in 2011, Shi and co-workers reported few examples on the NHC-Pd
[2], and Hartwig [3], the palladium-catalyzed
a-arylation of car-
bonyl compounds has been one of the most versatile methods for
the formation of C(sp2)–C(sp3) bonds [4–7]. Traditionally, in order
to improve the efficiency of such transformation, toxic, expensive,
less available, electron-rich and sterically-hindered monodentate
phosphine ligands were necessary. In addition, since Nolan’s initial
paper was reported in 2002, N-heterocyclic carbenes (NHCs),
which usually had the advantages of higher air-, moisture-, and
thermal-stability over their phosphine counterparts, were found
complex catalyzed
a-arylation of dialkyl ketones, in which
mono-arylated products can be only obtained when sterically
hindered 1-bromo-2-methoxynaphthalene or bulky (3-chlorophenyl)-
(phenyl)-methanone were used as the substrates [16]. Therefore,
much room still remains for the mono-arylation of symmetric
dialkyl ketones.
Recently, we have developed a well-defined and easily available
N-heterocyclic carbene-Pd(II)-1-methylimidazole [NHC-Pd(II)-Im]
to be excellent ligands in the palladium-catalyzed
a-arylation of
ketones [8–17]. However, despite the above abundant papers, the
mono-arylation of symmetric dialkyl ketones still kept a big chal-
lenge in organic synthesis [18–20]. For example, in 2011, Stradiotto
and co-workers reported the palladium-catalyzed mono-arylation
of acetone with aryl chlorides and tosylates using 1–6 mol% P,N
ligands [18]. In 2012, Ackermann and co-workers reported
the palladium-catalyzed mono-arylation of acetone with aryl
imidazolylsulfonates using 2-dicyclohexylphosphino-20,40,60-tri-
isopropylbiphenyl as the ligand, in high catalyst loadings
[5.0 mol% Pd(OAc)2 and 10.0 mol% ligand] [19]. In addition, all
complex 1 and found it to be efficient catalyst in the a-arylation
of aryl alkyl ketones, oxindoles and 2,3-dihydroinden-1-ones
[21–23]. In addition, we have also found that when 4-methoxy-
phenyl chloride 2a and 3-pentanone 3a were used as the sub-
strates, the solvents and reaction time drastically affected the
reaction. That is, when the ratio of 2a to 3a is 1.2:1 and the reaction
was performed in DMF for 6 h, the mono-arylated product 4a can
be obtained in 42% yield as the sole one, while if the same reaction
was performed in toluene for 3 h, the di-arylated product 5a can be
formed in 67% yield as the sole one (Scheme 1) [21]. These results
thus prompted us to further investigate the NHC-Pd(II)-Im com-
plex 1 catalyzed
chlorides. Herein, we report these results in detail.
a-arylation of symmetric dialkyl ketones with aryl
⇑
Corresponding author. Tel./fax: +86 577 86689300.
E-mail address: ljm@wzu.edu.cn (J.-M. Lu).
http://dx.doi.org/10.1016/j.ica.2014.07.061
0020-1693/Ó 2014 Elsevier B.V. All rights reserved.

Z.-K. Xiao et al. / Inorganica Chimica Acta 423 (2014) 106–108
107
OMe
DMF
O
MeO
Cl
Pri
6 h
NHC-Pd(II)-Im 1
4a, 42%
Pri
Pri
Cl
Pd
Cl
2a
+
(1.0 mol%)
O
N
N
KOtBu, 80 o
C
N
O
N
toluene
3 h
3a
Pri
2a/3a = 1.2/1
NHC-Pd(II)-Im 1
OMe
5a, 67%
OMe
Scheme 1. NHC-Pd(II)-Im complex 1 catalyzed reaction of 4-methoxyphenyl chlorides 2a with 3-pentanone 3a.
2. Experimental
Table 1
Optimization for the NHC-Pd(II)-Im complex
1
catalyzed mono-arylation of 3-
pentanone 3a with chlorobenzene 2b.
2.1. General remarks
Cl
1
NHC-Pd(II)-Im
Melting points are uncorrected. NMR spectra were recorded at
300/500 (for 1H NMR) or 75/125 MHz (for 13C NMR), respectively.
1H NMR and 13C NMR spectra recorded in CDCl3 solutions were ref-
erenced to TMS (0.00 ppm) and the residual solvent peak
(77.0 ppm), respectively. J-values are in Hz. Organic solvents used
were dried by standard methods. The mass analyzer type for the
high resolution mass spectra (HRMS) is quadrupole (for ESI). Other
commercially obtained reagents were used without further purifi-
cation. Flash column chromatography was performed on silica gel
(300–400 mesh).
(1.0 mol%)
+
O
O
KOtBu (2.0 equiv)
solvent, time, 80 o
C
4b
2b
3a
Entrya
2b:3a
Solvent
Time (h)
Yield (%)b
1
2
3
4
5
6
1.2:1
1.2:1
2:1
1:2
1:2
DMF
DMF
DMF
DMF
DMF
toluene
6
8
6
6
3
3
42
37
41
65
78
86
1:2
a
All reactions were carried out using 1 (1.0 mol%), KOtBu (2.0 equiv), solvent
2.2. General procedure for the NHC-Pd(II)-Im complex 1 catalyzed a-
arylation
(1.0 mL) at 80 °C.
b
Isolated yields.
Under N2 atmosphere, NHC-Pd(II)-Im complex
1 (6.5 mg,
1.0 mol%), KOtBu (224.4 mg, 2.0 mmol), toluene (1.0 mL), ketones
3 (2.0 mmol or 0.7 mmol), and aryl chlorides 2 (1.0 mmol) were
successively added into a Schlenk reaction tube. The mixture was
stirred at the specified temperature for the listed time shown in
Tables 1–3. The reaction mixture was cooled to room temperature,
then the solvent was evaporated under reduced pressure and the
residue was purified by flash column chromatography to give the
pure products.
Table 2
NHC-Pd(II)-Im complex 1 catalyzed mono-arylation of symmetric dialkyl ketones 3
with aryl chlorides 2.
O
R2
R2
R2
Cl
NHC-Pd(II)-Im 1
(1.0 mol%)
+
O
KOtBu (2.0 equiv)
toluene, 80 oC, 3 h
R1
R2
R1
2
4
3
3. Results and discussion
Entrya
2 (R1)
3 (R2)
Yield (%)b
Initial examinations were carried out using chlorobenzene 2b
and 3-pentanone 3a as the model substrates, KOtBu (2.0 equiv)
as the base, NHC-Pd(II)-Im complex 1 (1.0 mol%) as the catalyst,
DMF as the solvent at 80 °C for 6 h, and the mono-arylated product
4b can be obtained in 42% yield (Table 1, entry 1) [21], which still
kept in 41% when the ratio of 2b to 3a was adjusted to 2:1 (Table 1,
entry 3). When the reaction time was prolonged to 8 h, the yield of
4b was slightly decreased to 37% (Table 1, entry 2). In addition,
when the ratio of 2b to 3a was adjusted to 1:2, the yield of 4a
can be increased to 65% within 6 h (Table 1, entry 4). Considering
of the reversibility of this reaction as previously reported [21],
the reaction time was then decreased to 3 h, and the yield of 4a
can be actually increased to 78% (Table 1, entry 5). Finally, to our
pleasure, when toluene was used as the solvent, the best result
was achieved, giving product 4a in 86% yield (Table 1, entry 6).
With the optimal conditions in hand, we then set out to test the
reaction generality using a variety of aryl chlorides 2 and symmet-
ric dialkyl ketones 3 such as 3-pentanone 3a and 5-nonanone 3b as
the substrates. As can be seen from Table 2, all reactions took place
well to give the expected mono-arylated products 4 in good to high
yields. Substituents on the aryl chlorides had almost no effect on
1
2
3
4
5
6
7
8
2a (4-OMe)
2c (4-Me)
2d (3-Me)
2e (2-Me)
2f (2,6-Me2)
2g (4-F)
2h (3-OMe)
2i (2-OMe)
2j (4-NMe2)
2a
3a (Me)
3a
3a
3a
3a
4a, 86
4c, 83
4d, 82
4e, 89
4f, 89
4g, 80
4h, 90
4i, 89
4j, 87
4k, 83
4l, 95
4m, 79
4n, 80
4o, 87
3a
3a
3a
3a
9
10
11
12
13
14
3b (nPr)
3b
2b (H)
2c
2h
2i
3b
3b
3b
a
All reactions were carried out using 2 (1.0 mmol), 3 (2.0 mmol), 1 (1.0 mol%),
KOtBu (2.0 equiv), toluene (1.0 mL) at 80 °C for 3 h.
b
Isolated yields.
the reactions. For example, whether electron-rich substituents
such as Me, OMe, NMe2 or electron-poor substituent such as F
atom were attached on the phenyl rings of aryl chlorides, all reac-
tions gave products 4 in good to high yields. In addition, sterically-
hindered substituents such as 2-Me, 2-OMe, even 2,6-Me2 on the

108
Z.-K. Xiao et al. / Inorganica Chimica Acta 423 (2014) 106–108
Table 3
chlorides as the substrates, providing an alternative, phosphine-free
method for the mono-arylation of symmetric dialkyl ketones. It may
be noted here that this is the first example of phosphine-free, NHC-
NHC-Pd(II)-Im complex 1 catalyzed mono- and di-arylation of symmetric dialkyl
ketones 3 with aryl chlorides 2.
O
Pd complex catalyzed
a-mono-arylation of symmetric dialkyl
O
Cl
R2
R1
R2
R1
R2
R2
R1
ketones with such broad reaction generality. In addition, by tuning
the ratio of aryl chlorides and symmetric dialkyl ketones, the
mono-arylated and di-arylated products can be formed in good to
high total yields at the same time, with the latter as the major.
NHC-Pd(II)-Im 1
2
(1.0 mol%)
+
+
KOtBu (2.0 equiv)
O
toluene, 80 o
C
R2
R2
R1
5
4
3
Acknowledgements
Entrya
2 (R1)
3 (R2)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
2b (H)
3a (Me)
3a
3a
3
3
3
3
12
12
12
4b, 19
4c, 20
4d, 11
4e, 32
4m, 19
4p, 22
4k, 16
5b, 68
5c, 66
5d, 78
5e, 50
5f, 67
5g, 65
5h, 71
Financial support from the National Natural Science Foundation
of China (No. 21002072) is greatly appreciated.
2c (4-Me)
2d (3-Me)
2e (2-Me)
2c
3a
3b (nPr)
3b
Appendix A. Supplementary data
2d
2a (4-OMe)
3b
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.ica.2014.07.061.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
a
All reactions were carried out using 2 (1.0 mmol), 3 (0.7 mmol), 1 (1.0 mol%),
KOtBu (2.0 equiv), toluene (1.0 mL) at 80 °C.
b
Isolated yields.
phenyl rings of aryl chlorides had no effect on the reactions
(Table 2, entries 4, 5, 8 and 14).
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between aryl chlorides 2 and symmetric dialkyl ketones 3, we then
turned our interest to the di-arylation reaction. Though in our pre-
liminary investigations, when the reaction between 4-methoxy-
phenyl chloride 2a (1.5 mmol) and 3-pentanone 3a (1.0 mmol)
was performed in toluene for 3 h, the di-arylated product 5a can
be obtained in 80% yield as the sole one [21], after some trials
and errors, the best result can only be observed under such condi-
tions. However, to our disappointment, using other aryl chlorides
as the substrates, the di-arylated products cannot be formed as
the sole one. That is, under these conditions, the di-arylated prod-
ucts 5 were obtained as the major, along with the mono-arylated
products 4 as the minor. The results were shown in Table 3. It
seems that substituents on the aryl chlorides did not affect the
reactions. For all the aryl chlorides examined, all reactions per-
formed well to give the mono-arylated products 4 and di-arylated
products 5 in good to high total yields, with the latter as the major.
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4. Conclusion
In conclusion, NHC-Pd(II)-Im complex 1 was found to be an effi-
cient catalyst for the
Under the optimal conditions, the mono-arylated products can be
obtained in good to high yields as the sole using a variety of aryl
a .
-arylation of symmetric dialkyl ketones1
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1
Many efforts were tried for the mono- or di-arylation of other simple ketones
such as acetone and cyclohexanone under the optimal or other reaction conditions,
but no satisfactory result was achieved for these two substrates.