Direct route to 1,3-diketones by palladium-catalyzed carbonylative coupling of aryl halides with acetylacetone

Article abstract of DOI:10.1002/chem.201303872

Man up your magnesium! By employing a MgCl₂/Et₃N system, aryl diketones can be generated from the Pd-catalyzed carbonylative α-arylation of acetylacetone with aryl bromides (see scheme). The method is ideal for the introduction of carbon isotopes into more complex structures, since only stoichiometric amounts of carbon monoxide are employed. Copyright

Full text of DOI:10.1002/chem.201303872

COMMUNICATION
DOI: 10.1002/chem.201303872
Direct Route to 1,3-Diketones by Palladium-Catalyzed Carbonylative
Coupling of Aryl Halides with Acetylacetone
Signe Korsager,[a] Dennis U. Nielsen,[a] Rolf H. Taaning,[a] Anders T. Lindhardt,*[b] and
Troels Skrydstrup*[a]
The development of new synthetic protocols for accessing
1,3-diketones is always of high interest, as such structural
motifs represent excellent platforms or advanced building
blocks for the preparation of a number of heterocyclic com-
pounds of pharmaceutical and agrochemical interest.[1] Tra-
ditionally, the synthesis of 1,3-diketones relies on an aldol
reagent (Scheme 1a). Furthermore, in the latter case, the de-
veloped conditions proved unsuitable with ketones, such as
acetone or acetophenone, affording low yields of the desired
1,3-diketones.
Recently, the group of Beller published an interesting pro-
tocol for the Pd-catalyzed carbonylative a-arylation, which
reaction between
a carbonyl
compound and an enolate fol-
lowed by oxidation of the
formed alcohol.[2] Alternatively,
enolates have been reacted
with activated carboxylic acids
leading directly to the 1,3-dike-
tones.[3–5] However, both ap-
proaches are not without draw-
backs, which include limited
starting material availability, re-
stricted functional-group toler-
ance and the use of strong base.
We and others have reported
the direct Pd-catalyzed synthe-
sis of 1,3-diketones via a carbon-
ylative a-arylation of eno-
lates.[6–7] However, these trans-
formations were restricted to
the use of malonate derivatives
or by the need for strong base
(NaHMDS) in the case of
simple ketones to insure com-
plete formation of the enolate
Scheme 1. Palladium-catalyzed a-arylation coupling conditions affording 1,3-diketones and b-keto esters. cod=
1,5-cyclooctadiene; dba=dibenzylideneacetone.
demonstrated that indeed acetone and acetophenones can
act as viable enolate coupling partners with Cs2CO3 as the
[a] S. Korsager, D. U. Nielsen, Dr. R. H. Taaning, Prof. Dr. T. Skrydstrup
Center for Insoluble Protein Structures (inSPIN)
Interdisciplinary Nanoscience Center (iNANO)
and Department of Chemistry, Aarhus University
Gustav Wieds Vej 14, 8000 Aarhus C (Denmark)
Fax : (+45)8619-6199
base (Scheme 1b).[8] This improved reactivity of such sub-
strates was nevertheless compromised by the need of per-
forming the reaction with the reacting ketone as the solvent.
Moreover, the developed conditions were performed with
aromatic iodides as the electrophile and long reaction times
(up to 36 h) were needed. Hence, the development of alter-
native procedures might still prove useful.
E-mail: ts@chem.au.dk
[b] Dr. A. T. Lindhardt
Interdisciplinary Nanoscience Center (iNANO)
Biological and Chemical Engineering
Department of Engineering, Aarhus University
Finlandsgade 22, 8200 Aarhus N (Denmark)
Fax : (+45)4189-3001
Herein, we wish to report a mild and selective route to
1,3-diketones by a three-component Pd-catalyzed carbonyla-
tive a-arylation of acetylacetone with aryl bromides. Substi-
tuted aliphatic 1,3-diketones and 1-aryl-1,3-butadiones all
proved reactive under the developed conditions affording
the desired substituted diketones in high isolated yields. The
E-mail: lindhardt@chem.au.dk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201303872.
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developed method is ideal for isotope labeling as CO is de-
livered in stoichiometric amounts to the carbonylative reac-
tion by ex situ generation.[9] In this manner, 13C-labeled 1,3-
diketones were obtained and even an example of a double-
labeled 1,3-diketone is presented.
as the nucleophile, the results of which are depicted in
Table 1. Both electron-rich and deficient aryl bromides cou-
pled successfully leading to high carbonylative coupling
Table 1. Carbonylative a-arylation of acetylacetone with aryl halides.[a]
We recently reported that the combination of Et3N,
MgCl2, and the potassium monoester salts of malonates re-
acted excellently as enolate surrogates in the palladium-cat-
alyzed carbonylative a-arylation of aryl bromides and elec-
tron-deficient aryl chlorides (Scheme 1c).[10–11] Acidic
workup caused the intermediately formed acylated malonate
derivatives to decarboxylate forming the desired b-ketoest-
ers in high yields. We speculated as to whether this approach
could be extended to include the synthesis of the corre-
sponding 1,3-diketones. An indication was provided by the
reaction of ethyl acetoacetate with 4-bromobenzonitrile, se-
lectively affording the ethyl b-ketoester (1) upon acidic hy-
drolysis in an 83% isolated yield (Scheme 1d). Gratifyingly,
when acetylacetone was subjected to the developed reaction
conditions, the desired triketone was formed exclusively, as
1
observed by H NMR spectroscopic analysis of the crude re-
action mixture. Selective deacetylation by applying HCl
(2m) at 808C proved superior to treatment with formic acid
and a 96% isolated yield of (1) was secured after column
chromatography (Scheme 2).
Scheme 2. Optimized conditions for the carbonylative coupling of 4-bro-
mobenzonitrile with acetylacetone.
Notably, none of the corresponding debenzoylated prod-
uct was observed after acid hydrolysis.[12] Adding less than
one equivalent of MgCl2 caused a significant drop in selec-
tivity with isolation of both 2 and 4-cyanobenzoic acid, after
acidic treatment, presumably obtained through hydrolysis of
the vinyl benzoate.[10,13] With no added MgCl2, 4-cyanoben-
zoic acid was formed exclusively in 86% isolated yield (see
the Supporting Information). Finally, attempts to lower the
catalytic loading resulted in an incomplete reaction in com-
bination with loss of selectivity.
[a] Reaction conditions: Chamber A: Aryl halide (0.5 mmol), [PdCl2-
AHCTUNGTRENNUNG
CHTUNGTRENNUNG
AHCTUNGTRENNUNG
18 h. [b] Deacetylation with HCl performed at 908C. [c] Reaction per-
formed by using 4-chlorobenzonitrile as the substrate at 1208C in 36 h in
butyronitrile with Cy2NMe as the base. [d] Reaction run with aryl triflate
as substrate. [e] Reaction run at 1008C with Cy2NMe as the base.
[f] Electrophile (0.25 mmol). [g] Reaction run on a 3 mmol scale by using
With the conditions described in Scheme 2 in hand
a series of aryl bromides were tested against acetylacetone
2.5 mol% of [PdCl2ACTHNUGRTENUNG(cod)] and 2.5 mol% of Xantphos.
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Direct Route to 1,3-Diketones
COMMUNICATION
Table 3. Carbonylative a-arylation of different 1,3-dicarbonyl compounds
yields (4–5, 8–9, 12, and 2, 6–7, 13–16, respectively). Increas-
ing the reaction temperature to 1008C, while substituting
Et3N for Cy2NMe, was required to ensure proper reactivity
of ortho-substituted aryl bromides (18–22).[14] Heterocyclic
aryl bromides also proved effective affording isolated yields
of the desired 1,3-diketones in the range of 60–99% (com-
pounds 22–26). 1,4-Dibromobenzene underwent a double-
coupling to produce the symmetrical diketone 27 in quanti-
tative yield. One aryl triflate was also tested as the electro-
phile affording the desired product 9 in a 93% isolated
yield. Finally, an excellent 91% isolated yield of 2 starting
from 4-chlorobenzonitrile, was obtained, but required a reac-
tion temperature of 1208C and Cy2NMe as the base in bu-
tyronitrile to ensure full conversion.
with aryl bromides.[a]
Different 1,3-dicarbonyls were then evaluated as the cou-
pling partner in the carbonylative a-arylation (Table 2). To
our delight, substituents at the a-position on the pentane-
Table 2. Carbonylative a-arylation of different 1,3-dicarbonyl compounds
with aryl bromides.[a]
[a] Reaction conditions: Chamber A: Aryl bromide (0.5 mmol), [PdCl2-
AHCTUNGTRENNUNG
CHTUNGTRENNUNG
AHCTUNGTRENNUNG
18 h. [b] Reaction run at 1008C with Cy2NMe as the base. [c] No addition
of MgCl2.
tanoic acid derivatives (38 and 39), again, with no sign of
the debenzoylated product. The triketone derivatives 33 and
37 resemble the well-known herbicides, mesotrione and sul-
cotrione, with similar ring-opened soil metabolites, such as
38 and 39.[15]
The substituted acetylacetone products obtained in
Tables 1 and 2, could in principle, act as substrates in a se-
quential carbonylative a-arylation. This was achieved by
a simple raise in reaction temperature to 1008C and both
1,3-diaryl-1,3-propandiones 40 and 41 were secured in satis-
factory isolated yields of 72 and 68%, respectively, which
demonstrated the usefulness of this protocol for the prepa-
ration of non-symmetrical 1,3-diaryl-1,3-diketones.
[a] Reaction conditions: Chamber A: Aryl bromide (0.5 mmol), [PdCl2-
ACHTUNGTRENNUNG
CTHUNGTRENNUNG
(0.0375 mmol), P
18 h.
ACHTUNGTRENNUNG
2,4-dione core did not interfere with the reaction affording
the products 29–31 in acceptable yields as illustrated in
Table 2. Omitting the acidic treatment step led to the isola-
tion of triketones in yields reaching quantitative (Table 3). It
was observed that 1,3-diketones obtained by using ortho-
substituted aryl bromides required higher temperatures to
complete the acidic deacetylation. In the case of 1-bromo-2-
fluorobenzene, no deacetylation occurred leading to the sole
isolation of the triketone 36 in 86% yield. In addition, cyclic
1,3-diketones proved reactive affording the corresponding
triketones in high yields (32, 33, and 37). Interestingly, and
in contrast to reactions with acetylacetone, the addition of
MgCl2 was not required in the carbonylative reaction of to-
sylated 4-bromophenol leading to 37. Acidic treatment of 33
and 37 led to the corresponding ring-opened 5,7-diketohep-
As all carbonylative reactions presented in this work have
been performed by using only 1.5 equivalents of CO, the
method can, therefore, be effectively adapted for isotope la-
beling.[9] Applying 13CO from 13COgen, and starting with 4-
chlorobromobenzene (3 mmol) the corresponding 1,3-dike-
tone 13C-43 was obtained in an 89% isolated yield
(Table 4).[16] Repeating the sequence in the coupling to 4-
bromoveratrole afforded the double 13C-labeled 1,3-diaryl-
1,3-propandione 13C2-41 in a 78% (750 mg) isolated yield.
Subjecting 13C2-41 to either hydrazine or hydroxylamine pro-
duced the corresponding double-13C2-labeled 3,5-diarylpyra-
zole or 3,5-diarylisoxazole heterocycles in 81 and 89% iso-
lated yields (13C2-44 and 13C2-45).
Next, it was decided to test the suitability of the devel-
oped conditions for scale-up purposes, and hence the car-
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A. T. Lindhardt, T. Skrydstrup et al.
Table 4. Synthesis, labeling and application of 1,3-diaryl-1,3-propan-
diones.
Figure 1. Possible catalytic cycle for the carbonylative a-arylation with or
without added MgCl2.
Without added MgCl2, competing attack will occur through
the now more reactive oxygen affording the vinyl benzoate
D, which upon acidic treatment provides the corresponding
benzoic acid.[13]
In conclusion, reaction conditions were successfully devel-
oped for the carbonylative a-arylation of acetylacetone with
aryl bromides. The desired 1,3-diketones were obtained by
selective deacetylation of the intermediary formed triketone
under acidic conditions. All 1,3-diketones were isolated in
high yields and the catalytic conditions performed with ex-
cellent functional-group tolerance. The initially isolated 1-
aryl-1,3-diketones could, under near identical conditions, be
transformed into their corresponding 1,3-diaryl-substituted
1,3-propandiones. Finally, isotope labeling with 13CO afford-
ed a double 13C-labeled diketone, which was applied towards
the synthesis of heterocycles.
bonylative coupling protocol was applied to the synthesis of
4-(3-oxobutanoyl)benzonitrile 2. Initial studies on a 3 mmol
scale indicated that the catalyst loading could be reduced to
0.5 mol% with no reduction in the product yield. Finally,
performing the reaction on a 30 mmol scale afforded the de-
sired 1,3-diketone 2 in 99% isolated yield (Scheme 3).
Experimental Section
4-(3-Oxobutanoyl)benzonitrile (2, Scheme 1)
Chamber A: In an argon filled glovebox, 4-bromobenzonitrile (91 mg,
0.5 mmol), [PdCl2ACTHNUTRGNEU(GN cod)] (7.1 mg, 0.025 mmol), Xantphos (14.5 mg,
0.025 mmol), acetylacetone (55 mg, 0.55 mmol), MgCl2 (57 mg,
0.6 mmol), dioxane (3.0 mL), and Et3N (280 mL, 2 mmol) were added in
this order to chamber A of the two-chamber system, COware.[16] The
chamber was sealed with a screwcap fitted with a Teflon seal.
Chamber B (1.5 equiv CO): In an argon filled glovebox, HBF4·P
ACHTUNGTRENNUNG(tBu)3
(10.9 mg, 0.0375 mmol), [PdCl2A(cod)] (10.7 mg, 0.0375 mmol), 9-methyl-
CTHUNGTRENNUNG
fluorene-9-carbonyl chloride (182 mg, 0.75 mmol), dioxane (3.0 mL), and
Cy2NMe (320 mL, 1.5 mmol) were added to chamber B of the two-cham-
ber system in that order. The chamber was sealed with a screwcap fitted
with a Teflon seal.
Scheme 3. Example of the gram-scale synthesis of 1,3-diketone
(30 mmol scale) and low catalyst loading.
2
The loaded two-chamber system was removed from the glovebox and
heated to 808C for 18 h. The reaction was quenched with 2m HCl (2 mL)
and stirred for 1 h at 808C. The two phases were separated and the water
phase was extracted three times with CH2Cl2. The combined organic
phases were dried over anhydrous NaSO4, filtrated, and concentrated
under vacuum. The crude residue was subjected to flash chromatography
by using pentane/CH2Cl2 (1:1–>CH2Cl2) as the eluent. This resulted in
90 mg (96% yield) of the title product obtained as a colorless solid.
1H NMR (400 MHz, CDCl3): d=15.91 (s, 1H), 7.95 (d, J=8.55 Hz, 2H),
A possible mechanistic scenario for the catalytic cycle is
illustrated in Figure 1. Starting with an oxidative addition
step followed by CO insertion affords complex A. Next, the
MgCl2-activated complex B attacks A by a nucleophilic acyl
substitution or by ligand exchange followed by reductive
elimination forming C in both cases. This triketone is then
deacetylated with aqueous HCl to form the 1,3-diketone.
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Direct Route to 1,3-Diketones
COMMUNICATION
7.73 (d, J=8.55 Hz, 2H), 6.19 (s, 1H), 2.24 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=195.7, 179.7, 138.7, 132.4, 127.4, 118.1, 115.3, 97.6,
26.3 ppm; HRMS: m/z: calcd for C11H9NO2: 188.0712 [M+H+]; found:
188.0709.
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[6] For some recent reviews on Pd-catalyzed carbonylations, see: a) X.-
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Acknowledgements
We thank the Danish National Research Foundation (grant no.
DNRF59), the Villum Foundation, the Danish Council for Independent
Research: Technology and Production Sciences, the Lundbeck Founda-
tion, the Carlsberg Foundation, and Aarhus University for generous fi-
nancial support of this work.
Keywords: 1,3-diketones
· carbonylation · homogenous
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Received: October 3, 2013
Published online: && &&, 0000
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A. T. Lindhardt, T. Skrydstrup et al.
Homogenous Catalysis
S. Korsager, D. U. Nielsen,
R. H. Taaning, A. T. Lindhardt,*
T. Skrydstrup* ................ &&&& — &&&&
Direct Route to 1,3-Diketones by
Palladium-Catalyzed Carbonylative
Coupling of Aryl Halides with Acety-
lacetone
Man up your magnesium! By employ-
ing a MgCl2/Et3N system, aryl dike-
tones can be generated from the Pd-
catalyzed carbonylative a-arylation of
acetylacetone with aryl bromides (see
scheme). The method is ideal for the
introduction of carbon isotopes into
more complex structures, since only
stoichiometric amounts of carbon mon-
oxide are employed.
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!