Palladium-catalyzed C-C bond formation to construct 1,4-diketones under mild conditions

Article abstract of DOI:10.1002/anie.201101638

Palladium can do it! A novel palladium-catalyzed reaction between the bulky α-carbon centers of two ketones has led to the construction of 2,3-diaryl-1,4-diketones by employing α-chloroketones as electrophiles and zinc ketone enolates as nucleophiles (see

Full text of DOI:10.1002/anie.201101638

DOI: 10.1002/anie.201101638
À
C C Coupling
À
Palladium-Catalyzed C C Bond Formation To Construct
1,4-Diketones under Mild Conditions**
Chao Liu, Yi Deng, Jing Wang, Yingying Yang, Shan Tang, and Aiwen Lei*
Carbon–carbon bond formation is the central transformation
in synthetic organic chemistry. Although there are a number
À
of strategies to construct C C bonds, nucleophilic substitution
is perhaps the oldest and most widely used of these methods.
These transformations typically involve primary alkyl halides
or tosylates as electrophiles to couple with a variety of
different nucleophiles.[1] Direct substitution of a leaving group
at a C(sp2) center is not possible, while substitution is well
known for secondary alkyl (C(sp3)) positions even though this
can still prove problematic.
Scheme 1. Approaches to 1,4-diketone synthesis between two carbonyl-
substituted methyl units.
Since the early 1970s, transition-metal-catalyzed cross-
coupling reactions have been widely used to couple C(sp2)
electrophiles with various carbon nucleophiles to form C-
2
[2]
À
(sp ) C bonds. Although a few examples exist, cross-
nucleophilic substitution is less straightforward with only one
known example, in which R3 is an alkyl group such as Me or
Et.[7] There are no known examples of nucleophilic substitu-
tion reactions forming 2,3-disubstituted 1,4-diketones where
R2 and R3 are both aryl groups.[8] Therefore, we suggest that
transition-metal catalysts can be used to accomplish this type
of bond formation (Scheme 1, Path II).
One approach is to use oxidative enolate homocoupling in
the presence of stoichiometric amounts of transition-metal
salts and other oxidants to gain access to symmetric 1,4-
dicarbonyl derivatives.[9] Furthermore, oxidative enolate
cross-coupling can be used to construct unsymmetric 1,4-
dicarbonyl compounds,[10] although the selectivity for the
unsymmetric cross-coupled products are moderate. Conse-
couplings involving secondary a-carbonyl alkyl halides (C-
3
À
(sp )) to construct C C bonds in the presence of transition-
metal catalysts are still rare.[3]
Reactions between a-carbonyl alkyl halides and metal
enolates are of high importance, as the products (1,4-
dicarbonyl compounds) are often common substructures of
natural products and precursors for five-membered hetero-
arenes.[4] In particular, the direct C C bond formation
À
between two carbonyl-substituted methyl groups to construct
1,4-diketones is an important example. Nucleophilic substi-
tution reactions have been used to form bonds between two
carbonyl-substituted methyl groups when the electrophile is a
primary a-carbonyl alkyl halide (Scheme 1, Path I, R3 = H).[5]
In some cases, when tin enolates and a-haloketones are used
as substrates, transition-metal salts are used as Lewis acids to
increase the yields and control the selectivity for 1,4-diketone
synthesis.[6] Formation of 2,3-disubstitued 1,4-diketones by
À
quently, C C bond formations between secondary a-carbonyl
alkyl electrophiles and metal ketone enolates to produce 2,3-
disubstituted 1,4-diketones under mild conditions and in a
highly selective manner is a major challenge. Herein, we
communicate our progress in this area by reporting the
À
palladium-catalyzed C C bond formation between substi-
[*] C. Liu, Y. Deng, J. Wang, Y. Yang, S. Tang, Prof. A. Lei
College of Chemistry and Molecular Sciences
Wuhan University, Wuhan 430072 (China)
Fax: (+86)27-6875-4067
tuted a-chloroketones and zinc ketone enolates to construct
2,3-diaryl 1,4-diketones in high yields under mild conditions.
Recently, our research group has reported that a-haloke-
tones can be employed as an oxidant in both oxidative
coupling reactions and oxidative carbonylation, thus indicat-
E-mail: aiwenlei@whu.edu.cn
Homepage: http://www.chem.whu.edu.cn/GCI_WebSite/
main.htm
À
ing that the transmetalations of both Pd X and palladium–
enolate bonds (generated from the oxidative addition of a-
haloketones to Pd0) with nucleophiles like arylzinc reagents
and arylboronic acids are very facile.[11] This finding indicates
that a-haloketones are poor coupling partners with nucleo-
philes in the presence of transition-metal catalysts. However,
the functionalization of a-haloketones is important. Both we
and the research group of Fu have been able to demonstrate
the direct functionalization of a-haloketones using Ni cata-
lysts. This methodology only worked with a-haloketones
substituted at the a position with an alkyl group or a hydrogen
atom.[3] No a-aryl-substituted substrates were applied, per-
Prof. A. Lei
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics
Chinese Academy of Sciences, 730000 Lanzhou (China)
[**] This work was supported by the National Natural Science
Foundation of China (21025206, 20832003, 20972118, and
20772093) and the “973” Project from the MOST of China
(2011CB808600). We are also grateful for the support from “the
Fundamental Research Funds for the Central Universities” and the
Program for New Century Excellent Talents in University (NCET).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101638.
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haps owing to the higher steric hindrance of the aryl group. To
The concentration was found to be important, as only 34% of
the desired product was formed with significant amounts of
the homocoupling by-products of both 1a and 2a when the
reaction was carried out at a higher concentration (Table 1,
entry 4). In the absence of a Pd catalyst, no desired coupling
product was observed and instead large amounts of
unchanged desyl chloride 2a and trace amounts of its
dehalogenation by-product were detected (Table 1, entry 5).
The ligand effect was examined too (Table 1, entries 6–13).
Flexible bidentate phosphine ligands were less effective
(Table 1, entries 6–9). The P-Olefin ligand and the trans,-
trans-dibenzylideneacetone (dba) ligand, which can both
accelerate reductive elimination, only gave poor yields of
the desired product (Table 1, entries 10 and 11).[13] In the case
of monodentate phosphine ligands, PPh3 in either
[PdCl2(PPh3)2] or [Pd(PPh3)4] precursors was more effective
than the electron-rich phosphine ligand PBu3 (Table 1,
entries 12–14).
use a-aryl-substituted haloketones as an electrophilic cross-
coupling partner instead of an oxidant, we sought a nucleo-
philic metal enolate which might favor transmetalation with
À
the Pd X bond instead of the palladium–enolate bond.
Subsequent reductive elimination would then release the
important 1,4-diketone compound. With this idea in mind, the
reaction of the zinc enolate of 4-methoxyphenylacetone
(prepared in situ) and desyl chloride 2a was used as the
model to test this new type of bond formation (Table 1). After
Table 1: Impact of reaction parameters on the cross-coupling of desyl
chloride (2a) with the zinc enolate of 4-methoxyphenylacetone.[a]
The procedure was later employed with other arylace-
tones using 2a as the electrophile (Table 2). Phenylacetone
offered the cross-coupling product in 89% yield (Table 2,
entry 2). The addition of electron-donating (p-OMe; Table 2,
entry 1) or electron-withdrawing groups (p-CF3; Table 2,
entry 4) to the 4-position on the phenylacetones gave
excellent yields. Carbon–halogen bonds could be well-toler-
ated under the coupling conditions (Table 2, entries 6 and 7)
and the desired cross-coupling product could be generated
even when an ester group was introduced (Table 2, entry 8). A
substrate bearing a more sterically bulky aromatic group also
afforded the desired product with an excellent yield (Table 2,
entry 9).
Entry
Base
[Pd]/ligand
Yield [%][b]
1
2
3
4
NaH
nBuLi
LiHMDS
NaHMDS
[PdCl2(dppf)]/–
[PdCl2(dppf)]/–
[PdCl2(dppf)]/–
[PdCl2(dppf)]/–
<5
<5
<5
98
(86,[c] 34[d])
n.d.
<5
<5
19
5
6
7
8
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
–
[PdCl2(CH3CN)2]/dppm
[PdCl2(CH3CN)2]/dppe
[PdCl2(CH3CN)2]/dppp
[PdCl2(CH3CN)2]/dppb
[PdCl2(CH3CN)2]/P-Olefin
[Pd(dba)2]/–
[PdCl2(CH3CN)2]/PBu3
[PdCl2(PPh3)2]/–
[Pd(PPh3)4]/–
9
12
20
11
13
75
73
10
11
12[e]
13
14
À
Next, we demonstrated this palladium-catalyzed C C
bond formations with other a-chloroketones (Table 3).
Firstly, 2b was employed to perform the cross-coupling with
two typical arylacetones. Good to excellent yields of the
desired cross-coupling products were obtained (Table 3,
entries 1 and 2). When 2c was employed as the substrate,
we found that the C(sp2)–Cl bonds in the electrophiles could
be well-tolerated and that the C(sp3)–Cl bond was much more
reactive than C(sp2)–Cl bonds in these substrates (Table 3,
entries 3 and 4). Even the C(sp2)–Br bonds were not as
reactive as C(sp3)–Cl bond when 2d was used as the substrate
and the desired cross-coupling products were obtained in
good yields (Table 3, entries 5 and 6). This outcome provides
the possibility for further functionalization of the coupling
products. In contrast to the nucleophiles (see above), the
electrophiles are more sensitive to the nature of the sub-
stituents on the aromatic rings. This effect can be seen when
the reaction with an electron-donating group (OMe; 2e)
proceeded well and produced the desired products in high
yields (Table 3, entries 7–9), while the strong electron-with-
drawing group (CF3) only afforded trace amounts of the
desired products (Table 3, entries 10 and 11).
[a] Unless otherwise noted, the reaction was carried out with 1a
(0.50 mmol), 2a (0.25 mmol), base (0.50 mmol), ZnCl2 (0.60 mmol),
catalyst (0.0125 mmol), ligand (0.0125 mmol), THF (2 mL), 458C, 12h.
[b] Yield determined by GC analysis with m-terphenyl as the internal
standard. [c] At room temperature. [d] The reaction was carried out on a
0.25 mmol scale in 0.5 mL of THF. [e] 0.025 mmol of PBu3. n.d.=not
determined, THF=tetrahydrofuran.
considerable efforts, we established that 5 mol% of
[PdCl2(dppf)] in THF effects this C C bond formation in an
À
excellent yield at 458C (98%; Table 1, entry 4). Table 1
illustrates the impact of a variety of reaction parameters on
the cross-coupling process. Firstly, the influence of the base
was investigated (Table 1, entries 1–4).[12] Sodium bis(trime-
thylsilyl)amide (NaHMDS) was found to be the most
effective base and gave excellent results. Other bases such
as sodium hydride and n-butyllithium proved ineffective, and
afforded less than 5% of the desired product. It was
interesting to find that lithium bis(trimethylsilyl)amide
(LiHMDS) was also ineffective.
Next, we sought to use 1,2-diaryl ethanones as substrates
in these cross-coupling reactions to form tetraaryl-substituted
1,4-diketones. These compounds are difficult to synthesize by
traditional methods. By employing our palladium-catalyzed
À
Upon decreasing the reaction temperature to room
temperature, the yield was lower (86%; Table 1, entry 4).
C C bond-formation conditions between a-chloroketones
and zinc ketone enolates, the tetraaryl-substituted 1,4-dike-
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À
À
Table 2: Scope of palladium-catalyzed C C bond formations to
Table 3: Scope of palladium-catalyzed C C bond formations to
construct 2,3-diaryl-1,4-diketones.[a]
construct 2,3-diaryl-1,4-diketones.[a]
Entry
1
Product 3
Yield [%][b] (d.r.)[c]
92 (1.0:1)
Entry
2
Product 3
Yield [%][b] (d.r.)[c]
1
2
3j, R1 =OMe, 98 (0.2:1)
3k, R1 =CF3, 68 (0:1)
3a
3b
3c
2b
2
3
89 (0.8:1)
88 (1.0:1)
3
4
3l, R1 =OMe, 59 (0.7:1)
3m, R1 =CF3, 85 (0.3:1)
2c
2d
2e
2 f
5
6
3n, R1 =OMe, 72 (0.5:1)
3o, R1 =CF3, 66 (0.4:1)
4
5
6
7
8
9
3d
3e
3 f
3g
3h
3i
95 (0.6:1)
99 (0.8:1)
91 (0.3:1)
97 (0.9:1)
97 (0.7:1)
95 (0.7:1)
7
8
9
3p, R1 =Me, 77 (0.6:1)
3q, R1 =F, 98 (0.8:1)
3r, R1 =CF3, 86 (0.1:1)
10
11
3s, R1 =OMe, trace[d]
3t, R1 =CF3, trace[d]
[a] Reaction conditions: ketone 1 (0.50 mmol), NaHMDS in THF (2.0m,
0.25 mL), ZnCl2 (0.60 mmol), a-chloroketone 2 (0.25 mmol), [PdCl2-
(dppf)] (0.0125 mmol, 5 mol%), THF (2 mL), 458C, 10–16h. [b] Yield of
isolated product. [c] Diastereomeric ratios determined by 1H NMR
spectroscopy. [d] Detected by GC-MS methods.
[a] Reaction conditions: ketone 1 (0.50 mmol), NaHMDS in THF (2.0m,
0.25 mL), ZnCl2 (0.60 mmol), desyl chloride (0.25 mmol), [PdCl2(dppf)]
(0.0125 mmol, 5 mol%), THF (2 mL), 458C, 10–16h. [b] Yield of isolated
product. [c] Diastereomeric ratios determined by 1H NMR spectroscopy.
À
Scheme 2. Palladium-catalyzed C C bond formation to form tetraaryl-
substituted 1,4-diketone (Reaction conditions: see Table 2; the right-
hand part of these products come from the corresponding electro-
philes.)
tones were obtain in a straightforward manner. The products
are illustrated in Scheme 2. Symmetric 1,2-diaryl ethanones
such as the commercially available 4,4’-dimethoxy deoxy-
anisoin were coupled with 2a and 2d to afford the coupled
products in high yields (3u, 3v; Scheme 2). Unsymmetric 1,2-
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7339

Communications
À
diaryl ethanones were also employed and offered the
corresponding 1,2,3,4-tetraayl-substituted 1,4-diketones in
good yields (3w, 3x; Scheme 2).
at 1714 cmÀ1 and 1683 cmÀ1 representing the C C coupling
product: the 1,4-diketone 3a. To our surprise, the reaction was
very fast and was finished within 10 minutes to afford the
coupling product 3a in a 92% yield (based on GC analysis).
The mechanism of this palladium-catalyzed cross-coupling
reaction is believed to involve oxidative addition, trans-
metalation, and reductive elimination. The overall fast
reaction rate indicates an unusually fast reductive elimination
of the two bulky a-carbon atoms on the ketones from the
palladium center. Such a facile elimination is unexpected and
inexplicable. Further investigation into the mechanism is
currently underway.
In the Paal–Knorr synthesis,[14] 1,4-diketones are used as
precursors for the preparation of five-membered hetero-
arenes such as pyrroles, furans, and thiophenes. We decided to
subject our products to the Paal–Knorr reaction and synthe-
size tetraaryl-substituted five-membered heteroarenes. Such
compounds are important structural motifs with many
interesting optoelectronic and biological properties, further-
more, they are found in a variety of natural products,
pharmaceuticals, and serve as versatile building blocks in
organic synthesis.[15] Other routes[16] involve the direct multi-
ple arylation of furans and thiophenes to get tetraaryl-
substituted heteroarenes as reported by the research groups
of Miura and Itami. Alternative methods have also been
reported.[17]
In conclusion, we have developed a novel palladium-
catalyzed C C bond formation between a-chloroketones and
zinc ketone enolates to construct 2,3-diaryl-substituted 1,4-
diketones under mild conditions. The complex [PdCl2(dppf)]
was shown to be an ideal catalyst and various ketones could
À
À
Our Paal–Knorr reaction involved heating 3v in toluene
at reflux with catalytic amounts of TsOH and the tetraaryl-
substituted furan 4a was obtained in 75% yield (Scheme 3).
also be employed. Reaction monitoring showed that these C
C bond formations between two bulky carbon centers are
surprisingly fast. In addition, two of the cross-coupling
products were used as precursors for the Paal–Knorr synthesis
to afford tetraaryl-substituted furan and pyrrole compounds.
Experimental Section
General procedure for the synthesis of 3a: 4-Methoxyphenylacetone
(82.0 mg, 0.50 mmol) was dissolved in THF (2.0 mL) and added to a
Schlenk tube (25 mL) under nitrogen and the tube was then placed in
an ice-water bath. Then a solution of NaHMDS (2.0m) in THF
(0.25 mL) was injected into the Schlenk tube via a syringe. With
stirring, ZnCl2 (81.8 mg, 0.60 mmol) was then added under nitrogen.
After stirring for 10 min, [PdCl2(dppf)] (9.1 mg, 0.0125 mmol) and
desyl chloride (2a, 57.7 mg, 0.25 mmol) were added, respectively. The
reaction was then heated up to 458C and stirred for 12 hours. After
completion of the reaction, it was quenched with diluted HCl solution
and extracted with ethyl acetate (3 ꢀ 10 mL). The organic layers were
combined and the pure product was obtained by flash column
chromatography on silica gel (petroleum ether/ethyl acetate = 5:1).
The yield of isolated product was 92% (d.r. = 1.0:1). 1H NMR
(300 MHz, CDCl3): d = 7.96 (d, J = 7.4 Hz, 2H), 7.85 (d, J = 7.4 Hz,
2H), 7.57–6.84 (m, 20H), 6.79 (d, J = 8.5 Hz, 2H), 6.71 (d, J = 8.5 Hz,
2H), 5.53 (d, J = 11.3 Hz, 1H), 5.14 (d, J = 11.0 Hz, 1H), 4.78 (d, J =
11.3 Hz, 1H), 4.54 (d, J = 11.0 Hz, 1H), 3.73 (s, 3H), 3.72 (s, 3H), 2.18
(s, 3H), 1.92 ppm (s, 3H). 13C NMR (75 MHz, CDCl3): d = 208.21,
206.95, 199.73, 197.96, 158.84, 136.91, 136.66, 136.35, 132.97, 132.87,
129.90, 129.83, 129.02, 128.86, 128.82, 128.61, 128.45, 128.41, 127.46,
127.03, 114.21, 114.03, 62.45, 61.01, 57.28, 55.11, 30.70, 29.33 ppm.
HRMS (MALDI): m/z calcd for C24H22O3 [M+Na]+: 381.1467; found:
381.1478.
Scheme 3. Synthesis of tetraaryl-substituted furan and pyrrole from
1,4-diketones. Ts=4-toluenesulfonyl.
The methoxy and bromo substituents on the phenyl rings
provided good potential for further functionalization to
extend the carbon chain and thus make a teraaryl-substituted
furan unit that could be used as a cell structure for polymers
and functional materials. The tetraaryl-substituted pyrrole 4b
was also prepared in 41% yield by heating 3u in hexylamine
at reflux (Scheme 3).
À
To gain greater insight into our palladium-catalyzed C C
bond formations, the reaction of 1a with 2a was monitored by
using ReactIR. The kinetic profile (Scheme 4) shows a peak
at 1703 cmÀ1 representing the desyl chloride 2a and two peaks
Received: March 6, 2011
Revised: May 18, 2011
Published online: July 7, 2011
Keywords: a-chloroketones · 1,4-diketones · enolate coupling ·
.
Paal–Knorr reaction · palladium
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