Copper catalyzed arylation/C-C bond activation: An approach toward α-aryl ketones

Article abstract of DOI:10.1021/ja1033777

An efficient arylation/C-C activation process was discovered. -Diketones with aryl halides (aryl iodides and aryl bromides) could undergo reaction smoothly in the presence of Cu(I) or Cu(II) salts in DMSO using K3 PO4 3H2 O without ligands. The role of H2 O was unprecedented, which assisted the C-C activation. Various -aryl ketones could be efficiently synthesized by this novel method. In situ monitoring of the formation of KOAc and experimentation relating to "a classic diagnostic technique for the participation of radical anion intermediates" revealed the preliminary mechanistic information for the reaction. This method is simple, general, and practical which complemented the classic method for the rapid construction of C-C bonds to a carbonyl moiety.

Full text of DOI:10.1021/ja1033777

Published on Web 06/02/2010
Copper Catalyzed Arylation/C-C Bond Activation: An Approach toward
r-Aryl Ketones
Chuan He,† Sheng Guo,† Li Huang,† and Aiwen Lei*,†,‡
College of Chemistry and Molecular Sciences, Wuhan UniVersity, Wuhan, 430072, P. R. China and State Key
Laboratory for Oxo Synthesis and SelectiVe Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, 730000, Lanzhou, P. R. China
Received April 21, 2010; E-mail: aiwenlei@whu.edu.cn
Transition-metal-catalyzed selective C-C bond activation (cleav-
age) currently fascinates organometallic chemists, due to not only
its fundamental scientific interest but also its potential usage in
organic synthesis.1-4 Because of the inertness of C-C bonds, only
a few examples of the catalytic activation of C-C bonds have been
reported before 2000.3,5 In recent years, significant progress has
been achieved, which involved some effective strategies to activate
the C-C bonds, such as employing the strained ring systems,6-13
directing by chelation groups,14-18 or by other means.19-35 Due
to an interest in the copper-catalyzed C-C bond formation/R-
arylation of carbonyl compounds, we accidentally discovered a
C-C bond activation, which meanwhile led to an efficient approach
toward R-aryl ketones under mild conditions (Scheme 1).
thioamide)-Cu complex as the catalyst precursor (eq 1) (see more
details in the Supporting Information). It was unexpected that the
direct arylation product 3-phenylpentane-2,4-dione 4a was not the
final product but the R-phenyl ketone 3a was produced instead, in
which an acyl group was cleaved.
Table 1. Reaction Parameters of 1a with 2aa
entry
catalyst
base
solvent
yield (%)b
1
2
3
4
5
6
7
8
Pincer CuCl
Pincer CuCl
Pincer CuCl
CuI
CuCl2
Cu(OAc)2 ·H2O
none
CuI
CuI
CuI
CuI
CuI
CuI
CuI/TMEDA
CuI/DMEDA
K2CO3
Cs2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
60
71
87
98
91
92
NR
NR
NR
82
K3PO4 ·3H2O
K3PO4 ·3H2O
K3PO4 ·3H2O
K3PO4 ·3H2O
K3PO4 ·3H2O
none
K3PO4 ·3H2O
K3PO4 ·3H2O
K3PO4 ·3H2O
K3PO4 ·3H2O
K3PO4 ·3H2O
K3PO4 ·3H2O
K3PO4 ·3H2O
Scheme 1. Approach to the R-Aryl Ketones
9c
10
11
12
13
14d
15e
DMA
48
toluene
dioxane
DMSO
DMSO
NR
NR
42
46
a Reaction conditions: 1a (1.0 mmol), 2a (3.0 mmol), base (3 equiv),
copper catalyst (10 mol %) in DMSO at 90 °C for 20 h. b GC yields.
c At 60 °C. d TMEDA (20 mol %) was added. e DMEDA (20 mol %)
was added.
The R-aryl carbonyl compounds are important components of
many pharmaceuticals and bioactive molecules. Buchwald and
Hartwig have pioneered the palladium-catalyzed arylation of a
variety of carbonyl compounds using aryl halides as electrophiles.36,37
Fu and Lei employed an alternative arylation strategy by using
R-halocarbonyl compounds and ArM to achieve the same goal.38,39
Because of the economic attractiveness and good functional group
tolerance, copper catalysts are remarkably advantageous in chemical
syntheses. Buchwald,40 Ma,41 and Kwong42 et al. have reported
the efficient arylations of ꢀ-dicarbonyl compounds catalyzed by
copper salts. To the best of our knowledge, no examples have been
described in literature of R-aryl ketones being prepared using a
copper catalyst from the direct arylation of simple ketones. As
shown in Scheme 1, we communicated herein our finding in
arylation/C-C bond activation, which illustrated an efficient
example of achieving R-aryl ketones using a simple copper salt as
the catalyst without ligands.
This arylation/C-C activation prompted us into investigating the
reaction parameters. Selected results were compiled in Table 1.
Compared with K2CO3 and Cs2CO3, K3PO4 ·3H2O was the best base
in promoting this reaction (Table 1, entries 1-3). Interestingly, CuI
alone gave the best results, in which the yield was up to 98% (Table
1, entry 4). Cu(I) and Cu(II) salts showed similar efficiency (Table
1, entries 4-6). When the reaction temperature was lowered to 60
°C, no reaction occurred (Table 1, entry 9). In DMF and DMA,
the reactions gave the desired products in low yields (Table 1,
entries 10-11), while no reactions occurred in toluene and dioxane
(Table 1, entries 12-13). Addition of TMEDA or DMEDA
inhibited the reaction (Table 1, entries 14-15).
The substrate scope toward this arylation/C-C bond activation
was further investigated, and the results were listed in Table 2. A
wide array of aryl iodides were examined in the reaction with
diketone 2a, and moderate to excellent yields were obtained in
producing the corresponding R-aryl ketones (Table 2). Iodobenzene
derivatives, which bear substituted groups such as methyl, i-propyl,
methoxyl, chloro, fluoro, alkoxycarbonyl, nitro, phenyl, etc. at para
positions, all reacted smoothly with 2a to afford the desired
corresponding products (Table 2, entries 2, 4-8, 10-11). It is
noteworthy that the free COOH group in 4-iodobenzoic acid 1i
was fairly compatible with these conditions to afford 82% of product
Our initial efforts focused on the direct coupling between aryl
halides 1a and ꢀ-diketone compounds 2a by using the (pincer
† Wuhan University.
‡ Chinese Academy of Sciences.
9
10.1021/ja1033777  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 8273–8275 8273

C O M M U N I C A T I O N S
Table 4. Reactions of Various ꢀ-Diketones 2 with Aryl Iodide 1ia
3i (Table 2, entry 9). 1-Iodo-3-methylbenzene 1c also reacted
smoothly in good yield (Table 2, entry 3). However, iodobenzene
derivatives with a functional group substituted at ortho positions
could not react with 2a.
Table 2. Reactions of 2a with Various Aryl Iodides 1a
entry
1
3
yield (%)b
1
2
3
4
5
6
7
8
9
Ar ) Ph
1a
1b
1c
1d
1e
1f
1g
1h
1i
3a
3b
3c
3d
3e
3f
3g
3h
3i
75
74
71
74
89
67
79
91
82
56
81
Ar ) p-Me-C6H4
Ar ) m-Me-C6H4
Ar ) p-i-Pr-C6H4
Ar ) p-MeO-C6H4
Ar ) p-Cl-C6H4
a Reaction conditions: 1h (1.0 mmol), 2 (3.0 mmol), K3PO4 ·3H2O (3
equiv), CuI (10 mol %) in DMSO at 90 °C for 20 h. b Isolated yields.
Ar ) p-F-C6H4
Ar ) p-COOEt-C6H4
Ar ) p-COOH-C6H4
Ar ) p-NO2-C6H4
Ar ) p-Ph-C6H4
the presence of L-proline as the ligand, which produced 4a in a
rather high yield.43 Thus, we speculated that the presence of H2O
in our reaction system assisted the C-C activation process.
Meanwhile, no C-C cleavage was observed when 4a was subjected
under the standard reaction conditions (eq 3).
10
11
1j
1k
3j
3k
a Reaction conditions: 1 (1.0 mmol), 2a (3.0 mmol), K3PO4 ·3H2O (3
equiv), CuI (10 mol %) in DMSO at 90 °C for 20 h. b Isolated yields.
To our delight, aryl bromides could also react with 2a smoothly
at 110 °C, and the results were listed in Table 3. Similarly, the
reactions of bromobenzene dervatives substituted at para positions
with various functional groups also took place smoothly with 2a.
The substrate 2-bromonaphthalene 1s also displayed good selectivity
to afford 64% of the product (Table 3, entry 8).
Table 3. Reactions of 2a with Various Aryl Bromides 1a
Bunnett et al. had investigated the “nucleophilic” replacement
of two halogens in dihalobenzenes without the intermediacy of
monosubstitution products under irradiation (a classic diagnostic
technique for the participation of radical anion intermediates).44
entry
1
3
yield (%)b
1
2
3
4
5
6
7
8
Ar ) Ph
1l
3a
3b
3c
3e
3f
3g
3l
74
42
36
50
61
55
72
64
Ar ) p-Me-C6H4
Ar ) m-Me-C6H4
Ar ) p-MeO-C6H4
Ar ) p-Cl-C6H4
1m
1n
1o
1p
1q
1r
1s
Ar ) p-F-C6H4
Ar ) p-CF3-C6H4
Ar ) p-Naphthyl-C6H4
3m
a Reaction conditions: 1 (1.0 mmol), 2a (3.0 mmol), K3PO4 ·3H2O (3
equiv), CuI (10 mol %) in DMSO at 110 °C for 20 h. b Isolated yields.
The Cu-catalyzed arylation/C-C activation of various ꢀ-dike-
tones was also investigated. When heptane-3,5-dione 2b or nonane-
4,6-dione 2c was employed as the nucleophile to react with 1h,
the C-C activation was also observed, which produced the desired
R-aryl ketones 3n and 3o in 70% and 58% yield, respectively (Table
4, entries 1-2). When R2 was the methyl group, the corresponding
arylation/C-C activation product 3p was obtained in 35% yield
(Table 4, entry 3). Interestingly, when unsymmetric ꢀ-diketones
2e and 2f were engaged in the system, the reactions exhibited
excellent selectivities; only an acetyl group was cleaved from the
ꢀ-diketones (Table 4, entries 4-5). No reaction occurred when 2g
was used as the nucleophile (Table 4, entry 6).
Figure 1. Distribution of bis-arylated 3t and monoarylated 3u with reaction
time of the reaction of 1t with 2a (eq 4).
As shown in eq 4 and Figure 1, 3t was clearly the intermediate for
the bis-arylated product 3u. This experimental data excluded the
participation of radical intermediates in the C-C bond cleavage
reaction.45,46
It is interesting for us to note that only a trace of C-C activation
product formed while a 40% yield of direct arylation product 4a
was isolated when the reaction was carried out under anhydrous
conditions (eq 2). In fact, Jiang et al. had described the reaction
between aryl iodides and 2a using CuI as a catalyst precursor in
A putative reaction pathway was listed in Scheme 2. ArX could
oxidatively add to the Cu(I) complex I to generate Cu(III)
intermediate II. In the presence of H2O, the C-C bond activation/
cleavage occurred, which led to the formation of intermediate III
9
8274 J. AM. CHEM. SOC. VOL. 132, NO. 24, 2010

C O M M U N I C A T I O N S
Scheme 2. Putative Mechanism of C-C Bond Activation
(Cleavage) in the Arylation
technique for the participation of radical anion intermediates”
revealed the preliminary mechanistic information for the reaction.
This method is simple, general, and practical which complemented
the classic method for the rapid construction of C-C bonds to a
carbonyl moiety. The detailed mechanism is currently under
investigation in our laboratory and will be reported in due course.
Acknowledgment. This work was supported by the National
Natural Science Foundation of China (20702040, 20832003,
20972118).
Supporting Information Available: Experiment details and spectral
data for all compounds are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) Crabtree, R. H. Chem. ReV. 1985, 85, 245–269.
(2) Rybtchinski, B.; Milstein, D. Angew. Chem., Int. Ed. 1999, 38, 871–883.
(3) Jun, C.-H. Chem. Soc. ReV. 2004, 33, 610–618.
(4) Jun, C.-H.; Park, J.-W. Top. Organomet. Chem. 2007, 24, 117–143.
(5) Halpern, J. Acc. Chem. Res. 1982, 15, 238–244.
(6) Murakami, M.; Takahashi, K.; Amii, H.; Ito, Y. J. Am. Chem. Soc. 1997,
119, 9307–9308.
and the release of KOAc. Reductive elimination of intermediate
III could produce the other Cu(I) intermediate IV, which would
finally produce the desired R-aryl ketones by reacting with the
diketone and regenerate the Cu(I) intermediate I species for the
next catalytic cycle. Another alternative pathway was discussed in
the Supporting Information.
To probe the feasibility of the pathway and detect the formation
of KOAc, we attempted to use in situ IR to monitor the reaction
between 1a and 2a. We were delighted to see that the kinetic profiles
clearly revealed not only the consumption of 2a and the formation
of 3a but also a new species increasing at peak 1583 cm-1 (Figure
2A) which was unambiguously assigned as KOAc by comparison
with an authentic sample of KOAc (Figure 2B).
(7) Kim, S.; Takeuchi, D.; Osakada, K. J. Am. Chem. Soc. 2002, 124, 762–
763.
(8) Kondo, T.; Kaneko, Y.; Taguchi, Y.; Nakamura, A.; Okada, T.; Shiotsuki,
M.; Ura, Y.; Wada, K.; Mitsudo, T.-a J. Am. Chem. Soc. 2002, 124, 6824–
6825.
(9) Perthuisot, C.; Edelbach, B. L.; Zubris, D. L.; Simhai, N.; Iverson, C. N.;
Muller, C.; Satoh, T.; Jones, W. D. J. Mol. Catal. A: Chem. 2002, 189,
157–168.
(10) Bart, S. C.; Chirik, P. J. J. Am. Chem. Soc. 2003, 125, 886–887.
(11) Matsumura, S.; Maeda, Y.; Nishimura, T.; Uemura, S. J. Am. Chem. Soc.
2003, 125, 8862–8869.
(12) Winter, C.; Krause, N. Angew. Chem., Int. Ed. 2009, 48, 2460–2462.
(13) Seiser, T.; Cramer, N. J. Am. Chem. Soc. 2010, 132, 5340–5341.
(14) Suggs, J. W.; Jun, C. H. J. Am. Chem. Soc. 1984, 106, 3054–3056.
(15) Liou, S.-Y.; van der Boom, M. E.; Milstein, D. Chem. Commun. 1998,
687–688.
(16) Chatani, N.; Ie, Y.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 1999, 121,
8645–8646.
(17) Jun, C.-H.; Moon, C. W.; Lee, D.-Y. Chem.sEur. J. 2002, 8, 2422–2428.
(18) Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41, 222–234.
(19) Asao, N.; Nogami, T.; Lee, S.; Yamamoto, Y. J. Am. Chem. Soc. 2003,
125, 10921–10925.
(20) Gunay, A.; Jones, W. D. J. Am. Chem. Soc. 2007, 129, 8729–8735.
(21) Horino, Y. Angew. Chem., Int. Ed. 2007, 46, 2144–2146.
(22) Kuninobu, Y.; Takata, H.; Kawata, A.; Takai, K. Org. Lett. 2008, 10, 3133–
3135.
(23) Lee, D.-Y.; Hong, B.-S.; Cho, E.-G.; Lee, H.; Jun, C.-H. J. Am. Chem.
Soc. 2003, 125, 6372–6373.
(24) Miller, J. A. Tetrahedron Lett. 2001, 42, 6991–6993.
(25) Mueller, C.; Iverson, C. N.; Lachicotte, R. J.; Jones, W. D. J. Am. Chem.
Soc. 2001, 123, 9718–9719.
(26) Najera, C.; Sansano, J. M. Angew. Chem., Int. Ed. 2009, 48, 2452–2456.
(27) Necas, D.; Tursky, M.; Kotora, M. J. Am. Chem. Soc. 2004, 126, 10222–
10223.
(28) Schmink, J. R.; Leadbeater, N. E. Org. Lett. 2009, 11, 2575–2578.
(29) Shimada, T.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 6646–6647.
(30) Takahashi, T.; Song, Z.; Hsieh, Y.-F.; Nakajima, K.; Kanno, K.-i. J. Am.
Chem. Soc. 2008, 130, 15236–15237.
(31) Terao, Y.; Nomoto, M.; Satoh, T.; Miura, M.; Nomura, M. J. Org. Chem.
2004, 69, 6942–6944.
Figure 2. (A) 3D-FTIR profiles of the reaction of 1a and 2a. (B) ConcIRT
spectra of the new component (black curve) and authentic sample of KOAc
(red curve).
Stoichiometric reaction of 2e with CuI was also investigated
under the standard reaction conditions without adding ArI. No
acetophenone was detected (eq 5), which revealed that the C-C
activation did not occur in the Cu(I) intermediate I (Scheme 2).
(32) Xu, Q.; Cheng, B.; Ye, X.; Zhai, H. Org. Lett. 2009, 11, 4136–4138.
(33) Zeevaart, J. G.; Parkinson, C. J.; de Koning, C. B. Tetrahedron Lett. 2007,
48, 3289–3293.
(34) Zhang, N.; Vozzolo, J. J. Org. Chem. 2002, 67, 1703–1704.
(35) Sugiishi, T.; Kimura, A.; Nakamura, H. J. Am. Chem. Soc. 2010, 132, 5332–
5333.
(36) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382–12383.
(37) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108–11109.
(38) Strotman, N. A.; Sommer, S.; Fu, G. C. Angew. Chem., Int. Ed. 2007, 46,
3556–3558.
(39) Liu, C.; He, C.; Shi, W.; Chen, M.; Lei, A. Org. Lett. 2007, 9, 5601–5604.
(40) Hennessy, E. J.; Buchwald, S. L. Org. Lett. 2002, 4, 269–272.
(41) Xie, X.; Cai, G.; Ma, D. Org. Lett. 2005, 7, 4693–4695.
(42) Yip, S. F.; Cheung, H. Y.; Zhou, Z.; Kwong, F. Y. Org. Lett. 2007, 9,
3469–3472.
In conclusion, we have revealed an efficient arylation/C-C
activation process. ꢀ-Diketones and aryl halides (aryl iodides and
aryl bromides) could undergo reaction smoothly in the presence of
Cu(I) or Cu(II) salts in DMSO using K3PO4 ·3H2O without ligands.
The role of H2O was unprecedented, which assisted the C-C
activation. Various R-aryl ketones could be efficiently synthesized
from this novel method. In situ monitoring of the formation of
KOAc and experimentation relating to “a classic diagnostic
(43) Jiang, Y.; Wu, N.; Wu, H.; He, M. Synlett 2005, 2731–2734.
(44) Bunnett, J. F.; Creary, X. J. Org. Chem. 1974, 39, 3611.
(45) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem.sEur. J.
2004, 10, 5607–5622.
(46) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954–6971.
JA1033777
9
J. AM. CHEM. SOC. VOL. 132, NO. 24, 2010 8275