Palladium-catalyzed carbonylative α-arylation for accessing 1,3-diketones

Article abstract of DOI:10.1002/anie.201107494

With a hint of CO: The first Pd-catalyzed carbonylative α-arylations of simple ketones with carbon monoxide is presented for the direct synthesis of 1,3-diketones (see scheme). The method uses only stoichiometric amounts of CO, and hence allows for the si

Full text of DOI:10.1002/anie.201107494

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DOI: 10.1002/anie.201107494
Palladium Catalysis
Palladium-Catalyzed Carbonylative a-Arylation for Accessing 1,3-
Diketones**
Thomas M. Gøgsig, Rolf H. Taaning, Anders T. Lindhardt, and Troels Skrydstrup*
The palladium-catalyzed coupling between aryl halides and
enolizable reagents has become a convenient method for the
construction of C(sp2)–C(sp3) bonds to generate allylic and
benzylic carbonyl derivatives, which are found in a vast
number of pharmaceuticals and bioactive compounds.[1]
Owing to the significant contributions from the groups of
Hartwig, Buchwald, and others, efficient protocols for the
direct a-arylation of ketones, esters, amides, aldehydes,
nitriles, malonates, etc. have been developed.[2] Furthermore,
Scheme 1. Direct approaches to 1,3-diketones. Bt=benzotriazole,
PFP=pentafluorophenyl.
the mechanistic understanding of the enolate binding modes
À
and the C C bond-forming reductive elimination step has
been clarified, enabling chemists to design specific variants of
the a-arylation.[3]
monoxide, which makes this approach highly adaptable for
the 13C labeling of one of the carbonyl groups of the 1,3-
diketone product.[8]
The addition of carbon monoxide into the catalytic cycle
of the a-arylation would provide a straightforward entry to b-
keto carbonyl compounds from simple aryl halides and
carbonyl derivatives having one or two protons in the
a position. In particular, the synthesis of 1,3-diketones is of
high importance, as such compounds exhibit biological
activity, serve as versatile building blocks, and act as attractive
platforms for accessing various heterocyclic compounds.[4]
Numerous strategies for the synthesis of 1,3-diketones have
been reported; these compounds are typically obtained by the
aldol condensation of an enolate and a carbonyl compound
followed by oxidation of the resulting 3-hydroxy ketone.
However, only a few approaches have been oriented towards
their direct synthesis (Scheme 1).[5] Previously, Tanaka and
Kobayashi reported on the intermolecular carbonylative a-
arylation of malonate derivatives under high pressures of
carbon monoxide (20 atm).[6,7] However, attempts to include
ketones were unsuccessful and instead resulted in the
alkoxycarbonylation of the enolate derivative to an acylated
enol.
To identify an effective catalytic system for the carbon-
ylative a-arylation of ketones, we examined the coupling of 4-
iodoanisole (2) and propiophenone (3).[9] A catalytic system
consisting of [Pd(dba)2] and rac-binap, traditionally used in
the a-arylation of ketones, was chosen as the starting
point.[10,2e] The reactions were run using a two-chamber
system with the ex situ generation of CO from 9-methyl-9H-
fluorene-9-carbonyl chloride (1), as earlier described.[8] The
addition of 1 to the CO-producing chamber in 1.5 equivalents
with respect to 2 combined with 5 mol% of catalyst, which
was composed of [Pd(dba)2] and HBF4P(tBu)3, and stoichio-
metric base resulted in good CO incorporation and a
promising 67% yield of 4 was obtained (Table 1, entry 1).
To avoid the competing aminocarbonylation and/or amina-
tion with NaHMDS, propiophenone, and NaHMDS were
premixed for 1 hour at ambient temperature before they were
added to the reaction mixture, as reported by Hartwig and co-
workers.[11,12] Changing the solvent to toluene resulted in
exclusive formation of the direct a-arylated product 5; this
result can be explained by the enhanced basicity of the
sodium enolate in nonpolar solvents (Table 1, entry 2). A
decrease in the temperature lowered the yield of the reaction
(Table 1, entry 3). Different bases such as NaH, KHMDS, and
LiHMDS were inferior to NaHMDS (Table 1, entries 4–6).
On the other hand, ligands possessing a rigid ferrocene
backbone gave cleaner reactions and excellent yields of 4
were secured when dppf and DiPrPF were employed (Table 1,
entries 7 and 10). A comparable yield was obtained when the
reaction was run with the ketone in a slight excess with
respect to the base (Table 1, entry 11).[13,14] An increase in the
steric bulk on the phosphines resulted in the formation of the
benzylic ketone 5 as the sole product, thus demonstrating the
delicate balance often observed in the design of palladium
catalysts (Table 1, entry 9). Finally, it is interesting to note
that attempts to run these reactions under an atmosphere of
Herein, we report on the identification of a catalytic
system based on palladium for an effective carbonylative a-
arylation strategy for the direct synthesis of 1,3-diketones
from aryl iodides and simple ketones. Notably, the method
relies on the use of only stoichiometric amounts of carbon
[*] T. M. Gøgsig, Dr. R. H. Taaning, Dr. A. T. Lindhardt,
Prof. Dr. T. Skrydstrup
Center for Insoluble Protein Structures (inSPIN), Interdisciplinary
Nanoscience Center (iNANO) and Department of Chemistry
Aarhus University, Langelandsgade 140, 8000 Aarhus C (Denmark)
E-mail: ts@chem.au.dk
[**] We thank the Danish National Research Foundation, the Lundbeck
Foundation, the Carlsberg Foundation, the iNANO and OChem
Graduate Schools, and Aarhus University for generous financial
support of this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107494.
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Table 1: Optimization of the carbonylative a-arylation.[a]
Entry
Ligand
Base
Ratio[b]
Yield[c]
4/5
1
(Æ)-binap
(Æ)-binap
(Æ)-binap
(Æ)-binap
(Æ)-binap
(Æ)-binap
dppf
PPFtBu
DtBuPF
DiPrPF
NaHMDS
NaHMDS
NaHMDS
NaH
10:1
>1:19
>19:1
>19:1
1:1
67
–
52
60
–
2[d]
3[e]
4
5
6
7
8
KHMDS
LiHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
8:1
–
>19:1
>19:1
>1:19
>19:1
>19:1
80
61
–
85
85
9
10
11[f]
DiPrPF
Scheme 2. Carbonylative a-arylation with a variety of aryl iodides.
[a] Chamber A: 1 (0.45 mmol), [Pd(dba)2] (5.0 mol%), HBF4P(tBu)3
(5.0 mol%), DIPEA (0.68 mmol) in THF (2 mL). Chamber B: 3
(0.66 mmol) and base (0.66 mmol) were premixed for 1 h in THF (2 mL)
at RT before being added to a mixture of 2 (0.3 mmol), ligand
(3.6 mol%), [Pd(dba)2] (3.0 mol%). The reaction mixture was stirred for
17 h at 708C. [b] Determined by 1H NMR analysis. [c] Yields of the
isolated product. [d] Toluene as solvent in Chamber B. [e] Reaction
conducted at 408C. [f] Base (0.60 mmol). binap=2,2’-bis(diphenyl-
phosphino)-1,1’-binaphthyl, DIPEA=diisopropylethylamine, dppf=1,1’-
bis(diphenylphosphino)ferrocene, PPFtBu=(2R)-1-{(1R)-1-[bis(1,1-
dimethylethyl)phosphino]ethyl}-2-(diphenylphosphino)ferrocene,
DiPrPF=1,1’-bis(diisopropylphosphino)ferrocene, DtBuPF=1,1’-bis(di-
tert-butylphosphino)ferrocene, THF=tetrahydrofuran.
Reaction conditions: Chamber A: 1 (0.75 mmol), [Pd(dba)2]
(5.0 mol%), HBF4P(tBu)3 (5.0 mol%), DIPEA (1.13 mmol) in THF
(3 mL). Chamber B: 3 (1.10 mmol) and NaHMDS (1.00 mmol) were
premixed for 1 h in THF (3 mL) at RT before being added to a mixture
of aryl iodide (0.50 mmol), DiPrPF (3.6 mol%), and [Pd(dba)2]
(3.0 mol%). The reaction mixture was stirred for 17 h at 708C.
HMDS=hexamethyldisilazane.
showed diminished levels of reactivity. For example, 4-
bromoanisole resulted in 65% conversion into the desired
1,3-diketone exclusively after a reaction time of 42 hours
(Scheme 3).
CO (balloon) provided lower coupling yields and surprisingly
a 1:1 mixture of 4 and 5.
With these optimized reaction conditions in hand, we set
out to test the generality of this reaction. Gratifyingly, a
variety of aryl iodides coupled successfully to propiophenone
(Scheme 2). Electron-rich aryl iodides proved especially
effective, thus providing the 1,3-diketones in almost quanti-
tative yields. Despite the catalyst poisoning often observed by
sulfur-containing motifs, the coupling of 4-iodothioanisole
gave the desired product 8 in a good 80% yield. The MOM-
protected 2-iodophenol performed particularly well to give
the 3-methyl flavone precursor 10 in an excellent 94% yield.
The electron-poor aryl iodides displayed a slightly inferior
performance, thus indicating that the CO incorporation is
dependent on the electronic properties of the arylpalla-
dium(II) intermediate formed after the oxidative addition.[14]
Nevertheless, good chemoselectivity was obtained in the
reactions of 3-bromo- and 3-chloroiodobenzene, 13 and 15,
respectively, which allow for the further functionalization of
the resulting 1,3-diketones. In addition, heterocyclic com-
pounds, such as thiophenes and pyridines, were equally
adaptable to the applied reaction conditions and formed the
carbonylated a-arylation products 16 and 17 in good yields.
On the other hand, the corresponding aryl bromides proved
less effective under the applied reaction conditions and
Scheme 3. 4-Bromoanisole in the carbonylative a-arylation.
Different ketones were then evaluated with the test
substrate 4-iodoanisole (2; Scheme 4). To our delight, these
ketones coupled smoothly when subjected to the optimized
carbonylative a-arylation conditions, thus further expanding
the scope of this reaction. Comparable results were produced
with dialkyl ketones after they were premixed with NaHMDS
for 1 hour (18–20). Furthermore, an increase in the steric bulk
on the a carbon to the carbonyl group did not affect the
outcome of the reaction, as with 21. In contrast, the reactions
of acetophenone and cyclohexanone led to complex reaction
mixtures, most likely as a result of a competing aldol reaction
during the coupling (results not shown). Finally, a satisfactory
74% yield of 22 was obtained in the coupling of 2-tetralone
with 2 after treatment of the resulting coupling product with
methyl iodide owing to an otherwise a problematic purifica-
tion.[15]
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quantitatively. Finally, carbon isotope labeling of the hetero-
cyclic core structure in [13C]-3,5-diphenylpyrazole 26 and
[13C]-3,5-diphenylisoxazole 27 was successfully achieved in
two steps starting from iodobenzene and 13C-labeled carbon
monoxide, which was generated ex situ in the two-chamber
system.[17]
In summary, the Pd-catalyzed carbonylative a-arylation of
ketones with aryl iodides provides a new route to 1,3-
diketones, which serve as direct precursors to important
building blocks and heterocyclic compounds. Furthermore,
this technique proves effective for carbon isotope labeling of
biologically relevant structures such as flavones, pyrazoles,
and isoxazoles. Protocols that allow for the expansion of this
approach to the use of esters and amides, as well as other aryl
halides are currently in progress and will be reported in due
course.
Scheme 4. Carbonylative a-arylation with different ketones. Reaction
conditions: Chamber A: 1 (0.75 mmol), [Pd(dba)2] (5.0 mol%), HBF4P-
(tBu)3 (5.0 mol%), DIPEA (1.13 mmol) in THF (3 mL). Chamber B:
ketone (1.10 mmol) and NaHMDS (1.00 mmol) were premixed for 1 h
in THF (3 mL) at RT before being added to a mixture of 2
(0.50 mmol), DiPrPF (3.6 mol%), and [Pd(dba)2] (3.0 mol%). The
reaction mixture was stirred for 17 h at 708C. The yields refer to the
isolated products.
Experimental Section
1-(2-(Methoxymethoxy)phenyl)-2-methyl-3-phenylpropane-1,3-
dione (10, Scheme 2): A two-chamber reactor was employed as
earlier described.[8a] In a glovebox, 9-methyl-9H-fluorene-9-carbonyl
chloride 1 (0.75 mmol), [Pd(dba)2] (5 mol%) and HBF4P(tBu)3
(5 mol%) were dissolved in THF (3 mL) in Chamber A. DIPEA
(diisopropylethylamine) (1.13 mmol) was then added and the cham-
ber was fitted with a Teflonꢀ sealed screwcap.
The fact that only a small excess of carbon monoxide was
used in the reaction prompted us to investigate the possibility
of exploiting this method for the 13C-labeling of 1,3-diketones.
As such compounds are viable precursors to a wide range of
heterocyclic compounds including pyrazoles, isoxazoles, and
flavones, this approach would represent a new strategy for the
synthesis of carbon-isotope-labeled heterocycles.[16]
A solution of the ketone (1.10 mmol) dissolved in THF (1 mL)
was added dropwise to a solution of NaHMDS (1.0 mmol) in 1 mL
THF. The reactor was fitted with a screwcap and the reaction mixture
was stirred at RT for approximately 1 h. In a glovebox, 1-iodo-2-
(methoxymethoxy)benzene (0.5 mmol), DiPrPF (3.6 mol%) and
[Pd(dba)2] (3.0 mol%) were dissolved in THF (1 mL) in Chamber
B. The generated enolate mixture was then added and this chamber
was also fitted with a Teflon sealed screwcap.
The 13C-labeled variant of the carboxylic acid chloride 1
prepared from 9-fluorenone was utilized as the carbon
monoxide precursor in 1.5 equivalents (Scheme 5).[8a] Starting
from MOM-protected 2-iodophenol, the 13C-labeled 1,3-
diketone 23 was obtained in a 90% yield. Subsequent
hydrolysis of the methoxymethyl ether protecting group and
dehydrative cyclization formed the 3-methyl flavone 24
The loaded two-chamber system was then removed from the
glovebox and heated at 708C for 17 h. The crude reaction mixture
from Chamber B was quenched with 1m HCl (0.7 mL) and water was
added. The aqueous phase was extracted three times with CH2Cl2.
The combined organic phases were dried over Na2SO4 and concen-
trated in vacuo. The crude product was purified by flash column
chromatography using 10% ethyl acetate in pentane as eluent to give
1
140 mg (94% yield) of the title product as a colorless oil. H NMR
(400 MHz, CDCl3): d = 8.03 (d, 2H, J = 7.8 Hz), 7.91 (dd, 1H, J = 1.7,
7.8 Hz), 7.60–7.56 (m, 1H), 7.49 (t, 2H, J = 7.8 Hz), 7.43–7.39 (m,
1H), 7.13 (d, 2H, J = 8.4 Hz), 7.05 (t, 1H, J = 8.4 Hz), 5.38 (q, 1H, J =
7.2 Hz), 4.82 (q, 2H, J = 7.1 Hz), 3.11 (s, 3H), 1.52 ppm (d, 3H, J =
7.2 Hz). 13C NMR (100 MHz, CDCl3): d = 197.8, 197.2, 156.4, 135.9,
134.2, 133.3, 131.4, 128.9, 128.7, 126.8, 122.1, 114.7, 94.2, 56.2, 54.7,
14.2 ppm. HRMS C18H18O4 [M+Na+]; calculated 321.1103, found
321.1105.
Received: October 24, 2011
Published online: December 5, 2011
Keywords: carbonylation · 1,3-diketones ·
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homogeneous catalysis · isotope labeling · palladium
[1] For reviews on palladium catalyzed a-arylation, see: a) D. A.
Culkin, J. F. Hartwig, Acc. Chem. Res. 2003, 36, 234; b) G. C.
Lloyd-Jones, Angew. Chem. 2002, 114, 995; Angew. Chem. Int.
Ed. 2002, 41, 953; c) C. C. C. Johansson, T. J. Colacot, Angew.
Chem. 2010, 122, 686; Angew. Chem. Int. Ed. 2010, 49, 676.
Scheme 5. Cyclizations of 13C-labeled 1,3-diketones. MOM=methoxy-
methyl.
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[2] For
a
representative selection see: a) B. C. Hamann, J. F.
[9] Electron-rich arylpalladium(II) intermediates are known to
Hartwig, J. Am. Chem. Soc. 1997, 119, 12382; b) M. Palucki,
S. L. Buchwald, J. Am. Chem. Soc. 1997, 119, 11108; c) T. Satoh,
J. Inoh, Y. Kawamura, Y. Kawamura, M. Miura, M. Nomura,
Bull. Chem. Soc. Jpn. 1998, 71, 2239; d) X. Liu, J. F. Hartwig, J.
Am. Chem. Soc. 2004, 126, 5182; e) K. H. Shaughnessy, B. C.
Hamann, J. F. Hartwig, J. Org. Chem. 1998, 63, 6546; f) K. D.
Hesp, R. J. Lundgren, M. Stradiotto, J. Am. Chem. Soc. 2011,
133, 5194; g) W. A. Moradi, S. L. Buchwald, J. Am. Chem. Soc.
2001, 123, 7996; h) J. Cossy, A. de Filippis, D. G. Pardo, Org. Lett.
2003, 5, 3037; i) G. D. Vo, J. F. Hartwig, Angew. Chem. 2008, 120,
2157; Angew. Chem. Int. Ed. 2008, 47, 2127; j) M. R. Biscoe, S. L.
Buchwald, Org. Lett. 2009, 11, 1773.
promote the carbon monoxide incorporation to a higher extent
than the corresponding electron-poor intermediates, see: a) P. E.
Garrou, R. F. Heck, J. Am. Chem. Soc. 1976, 98, 4115; b) T.
Ishiyama, H. Kizaki, T. Hayashi, A. Suzuki, N. Miyaura, J. Org.
Chem. 1998, 63, 4726; c) Y. Wan, M. Alterman, M. Larhed, A.
Hallberg, J. Org. Chem. 2002, 67, 6232.
[10] J. M. Fox, X. Huang, A. Chieffi, S. L. Buchwald, J. Am. Chem.
Soc. 2000, 122, 1360.
[11] T. Hama, J. F. Hartwig, Org. Lett. 2008, 10, 1549.
À
[12] Palladium-catalyzed C N couplings using LiHMDS as an
ammonia surrogate have been described in the literature, see:
S. Lee, M. Jørgensen, J. F. Hartwig, Org. Lett. 2001, 3, 2729.
[13] It has been demonstrated that the aldol product from the
condensation of aldehydes is reversible, releasing the reactive
enolate intermediate by a retro-aldol process, see: R. Martꢄn,
S. L. Buchwald, Angew. Chem. 2007, 119, 7374; Angew. Chem.
Int. Ed. 2007, 46, 7236.
[3] a) D. A. Culkin, J. F. Hartwig, Organometallics 2004, 23, 3398;
b) D. A. Culkin, J. F. Hartwig, J. Am. Chem. Soc. 2001, 123, 5816;
c) A. C. Albꢁniz, M. Catalina, P. Espinet, R. Redꢂn, Organo-
metallics 1999, 18, 5571.
[4] a) A. V. Kelꢃin, Curr. Org. Chem. 2003, 7, 1691; b) A. V. Kelꢃin,
A. Maioli, Curr. Org. Chem. 2003, 7, 1855.
[14] Similar trends have been reported by the group of Beller, see:
a) X.-F. Wu, H. Neumann, A. Spannenberg, T. Schulz, H. Jiao,
M. Beller, J. Am. Chem. Soc. 2010, 132, 14596; b) X.-F. Wu, P.
Anbarasan, H. Neumann, M. Beller, Angew. Chem. 2010, 122,
7474; Angew. Chem. Int. Ed. 2010, 49, 7316; c) X.-F. Wu, H.
Neumann, M. Beller, Chem. Eur. J. 2010, 16, 9750.
[15] N. A. Beare, J. F. Hartwig, J. Org. Chem. 2002, 67, 541.
[16] a) S. T. Heller, S. R. Natarajan, Org. Lett. 2006, 8, 2675; b) M.
Rowley, H. B. Broughton, I. Collins, R. Baker, F. Emms, R.
Marwood, S. Patel, S. Patel, C. I. Ragan, S. B. Freedman, P. D.
Leeson, J. Med. Chem. 1996, 39, 1943; c) X. Liu, C.-B. Chan, S.-
W. Jang, S. Pradoldej, J. Huang, K. He, L. H. Phun, S. France, G.
Xiao, Y. Jia, H. Luo, K. Ye, J. Med. Chem. 2010, 53, 8274.
[17] Patent application currently proceeding: T. Gøgsig, R. H.
Taaning, A. T. Lindhardt, T. Skrydstrup, (Aarhus University,
Denmark) Process for the synthesis of 1,3-dicarbonyl com-
pounds using carbon monoxide. PA 2011 70515, Sept. 20th, 2011.
[5] a) D. Lim, F. Fang, G. Zhou, D. M. Coltart, Org. Lett. 2007, 9,
4139; b) T. Fukuyama, T. Doi, S. Minamino, S. Omura, I. Ryu,
Angew. Chem. 2007, 119, 5655; Angew. Chem. Int. Ed. 2007, 46,
5559; c) K. Sato, S. Yamazoe, R. Yamamoto, S. Ohata, A. Tarui,
M. Omote, I. Kumadaki, A. Ando, Org. Lett. 2008, 10, 2405;
d) M. Sada, S. Matsubara, J. Am. Chem. Soc. 2010, 132, 432.
[6] T. Kobayashi, M. Tanaka, Tetrahedron Lett. 1986, 27, 4745.
[7] For intramolecular carbonylative a-arylations, see: a) E. Negishi,
C. Copꢁret, T. Sugihara, I. Shimoyama, Y. Zhang, G. Wu, J. M.
Tour, Tetrahedron 1994, 50, 425; b) E. Negishi, H. Makabe, I.
Shimoyama, G. Wu, Y. Zhang, Tetrahedron 1998, 54, 1095; c) Z.
Zheng, H. Alper, Org. Lett. 2009, 11, 3278.
[8] a) P. Hermange, A. T. Lindhardt, R. H. Taaning, K. Bjerglund,
D. Lupp, T. Skrydstrup, J. Am. Chem. Soc. 2011, 133, 6061; b) P.
Hermange, T. M. Gøgsig, A. T. Lindhardt, R. H. Taaning, T.
Skrydstrup, Org. Lett. 2011, 13, 2444; c) D. U. Nielsen, R. H.
Taaning, A. T. Lindhardt, T. M. Gøgsig, T. Skrydstrup, Org. Lett.
2011, 13, 4454.
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