Palladium catalyzed carbonylative Heck reaction affording monoprotected 1,3-ketoaldehydes

Article abstract of DOI:10.1021/ol300837d

The direct carbonylative palladium catalyzed synthesis of monoprotected 1,3-ketoaldehydes is reported starting from aryl iodides applying near stoichiometric amounts of carbon monoxide. Besides representing platforms for a variety of heterocyclic structures, these motives serve as viable precursors for the highly relevant aryl methyl ketones. The presented strategy can also be adapted for the facile and efficient incorporation of ¹³C-labeled carbon monoxide.

Full text of DOI:10.1021/ol300837d

ORGANIC
LETTERS
2012
Vol. 14, No. 10
2536–2539
Palladium Catalyzed Carbonylative Heck
Reaction Affording Monoprotected
1,3-Ketoaldehydes
Thomas M. Gøgsig, Dennis U. Nielsen, Anders T. Lindhardt, and Troels Skrydstrup*
Center for Insoluble Protein Structures (inSPIN), Department of Chemistry and the
Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Langelandsgade
140, 8000 Aarhus C, Denmark
ts@chem.au.dk
Received April 2, 2012
ABSTRACT
The direct carbonylative palladium catalyzed synthesis of monoprotected 1,3-ketoaldehydes is reported starting from aryl iodides applying near
stoichiometric amounts of carbon monoxide. Besides representing platforms for a variety of heterocyclic structures, these motives serve as
viable precursors for the highly relevant aryl methyl ketones. The presented strategy can also be adapted for the facile and efficient incorporation
of 13C-labeled carbon monoxide.
Olefins represent one of the most versatile functional
groups in organic chemistry serving as an indispensible
platform to a myriad of different chemical bond forma-
tions. The presence of CÀC double bonds in bioactive
compounds, fine chemicals, organic materials, etc. is vast,
emphasizing the importance of this functional group and
its functionalization.1
The palladium catalyzed direct substitution of the ole-
finic CÀH bonds, also known as the Heck reaction,
constitutes one of the most powerful Pd-catalyzed
reactions owing to the exceptional functional group toler-
ance and mild conditions often applied.2 Although the
Heck reaction has been subjected to considerable investi-
gations in recent decades, controlling regioselectivity still
poses a significant challenge, especially when neutral- and
electron-rich olefins are employed.3 In order to gain full
control of the regioselective outcome, it is essential to be
able to differentiate between the two catalytic pathways,
which are inherently competing during the catalytic cycle
of the Heck reaction. Traditionally, bidentate ligands have
been utilized in the regioselective arylation of electron-rich
olefins resulting in the cationic pathway, thus producing
(1) (a) Larock, R. C. In Comprehensive Organic Transformations: A
Guide to Functional Group Preparations, 2nd ed.; VCH: New York, 1999
and references cited therein. (b) Mackenzie, K. In The Chemistry of Alkenes;
Patai, S., Ed.; Wiley: New York, 1964. (c) Kricheldorf, H. R.; Nuyken, O.;
Swift, G. In Handbook of Polymer Synthesis, 2nd ed.; Marcel Dekker: New
York, 2005. (d) Handbook of Metathesis, Vols. 1À3; Grubbs, R. H., Ed.;
Wiley-VCH: Weinheim, 2003.
(2) (a) Hartwig, J. F. In Organotransition Metal Chemistry: From
Bonding to Catalysis; University Science Books: 2010. (b) For a review, see:
(a) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009. (b) de
Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. 1994, 33, 2379. For
Heck in total synthesis, see: (c) Dounay, A. B.; Overman, L. E. Chem.
Rev. 2003, 103, 2945.
(3) (a) Cabri, W.; Candiani, I.; Bedeschi, A. J. Org. Chem. 1990,
55, 3654. (b) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2.
(c) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(d) Schnyder, A.; Aemmer, T.; Indolese, A. F.; Pittelkow, U.;
Studer, M. Adv. Synth. Catal. 2002, 344, 495. (e) Fristrup, P.;
Quement, S. L.; Tanner, D.; Norrby., P.-O. Organometallics 2004,
23, 6160. (f) Mo, J.; Xu, L.; Xiao, J. J. Am. Chem. Soc. 2005, 127,
751. (g) Ruan, J.; Iggo, J. A.; Berry, N. G.; Xiao, J. J. Am. Chem.
Soc. 2010, 132, 16689.
r
10.1021/ol300837d
Published on Web 05/07/2012
2012 American Chemical Society

branched R-arylated alkenes.4 On the other hand, introdu-
cing monodentate ligands tends to produce mixtures of the
two regioisomers, when olefins such as butyl vinyl ether are
employed indicating both pathways are operative.3d,4a,5,6
Recently, Beller and co-workers disclosed the carbony-
lative Heck reaction of aryl halides and styrenes or vinyl
ethers relying on a catalytic system composed of palladium
and a bidentate ligand.7 Interestingly, in the couplings of
vinyl ethers the linear R,β-unsaturated ketoethers were
obtained exclusively implying that the insertion of carbon
monoxide into the catalytic cycle reverses the regioselective
outcome of the Heck reaction of electron-rich olefins.8 In
accordance to the literature, the relatively high pressures of
CO (5À10 bar) applied in this protocol increase the
demands imposed on the catalytic system. The employ-
ment of an imidazole-based phosphine developed by Beller
and co-workers was found to be mandatory in order to
secure an active catalytic system.7b,8,9 Formation of
carbonyl palladium clusters at high CO pressures slows
the rate of the overall reaction as the concentration of
the active catalyst is lowered, a hurdle which can be
overcome by the addition of extra phosphine.10 Hence,
lowering of the applied CO pressures, thereby prevent-
ing the formation of palladium carbonyl clusters,
would in general be beneficial in Pd-catalyzed carbon-
ylation chemistry.11
Based on our recent work dealing with the Pd-catalyzed
carbonylative Heck reaction of styrenes, we wish to report
on the regioselective aroylation of butyl vinyl ether apply-
ing carbon monoxide in a slight excess.12 The presented
strategy describes the direct formation of monoprotected
1,3-ketoaldehydes starting from aryl iodides without using
autoclaves and specialized safety equipment.13 In particu-
lar, 1,3-ketoaldehydes serve as valuable precursors to a
wide range of heterocyclic structures including pyrazoles,
pyrimidines, isoxazoles, etc. Furthermore, we found R,β-
unsaturated ketoethers to be immediate precursors to the
corresponding aryl methyl ketones further demonstrating
the applicability of these structures.
In order to secure a safe and efficient delivery of carbon
monoxide, the diatomic gas was generated externally in a
two-chamber system (COware) from 9-methyl-9-fluorene-
9-carbonyl chloride 1 (COgen) in the presence of Pd(dba)2
and HBF4P(t-Bu)3 combined with DIPEA (diisopropyl-
ethylamine) as previously reported.14,15 In the parallel CO-
consuming chamber preliminary investigations revealed
PdCl2 without the addition of phosphine ligands in the
presence of tertiary amine base Cy2NMe16 at 100 °C to be a
promising starting point facilitating the desired carbonyl-
ative Heck coupling of 4-iodotoluene and butyl vinyl ether
(Table 1, entry 1). However, significant amounts of the
reducedβ-aroylatedproduct weredetected, which could be
explained by the competing reductive Heck reaction.17
Table 1. Optimization of the Carbonylative Heck Reactiona
(4) (a) Ruan, J.; Xiao, J. Acc. Chem. Res. 2011, 44, 614.
(5) (a) Carrow, B. P.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 79.
(b) Datta, G. K.; von Schenk, H.; Hallberg, A.; Larhed, M. J. Org.
Chem. 2006, 71, 3896.
(6) The existence of anionic palladium species in the catalytic cycle
might also be responsible for the regioselective outcome of the Heck
reaction using sterically encumbered alkyl phosphine ligands such as
P(t-Bu)3. See ref 5a.
(7) (a) Wu, X.-F.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed.
2010, 49, 5284. (b) Wu, X.-F.; Neumann, H.; Spannenberg, A.; Schulz,
T.; Jiao, H.; Beller, M. J. Am. Chem. Soc. 2010, 132, 14596.
(8) During the preparation of this article, the group of Beller reported
the carbonylative Heck reaction of aryl bromides using vinyl ethers
applying a total pressure of 80 bar (5 bar of CO and 75 bar of N2). See:
Schranck, J.; Wu, X.-F.; Neumann, H.; Beller, M. Chem.;Eur. J. 2012,
18, 4827.
ligand
conversion ratio yieldb
entry
[Pd]
(mol %)
(%)
(2:3:4) (%)
1
2
3
4
5
6
7
8
9
PdCl2
À
À
À
À
À
>95
55
20:10:1
4:1:1
À
À
À
À
À
À
À
À
À
À
À
72
À
À
81
Pd(OAc)2
[(allyl)PdCl]2
Pd(dba)2
>95
50
10:3:1
20:3:1
20:5:1-
10:1:1
20:3:1
20:1:5
20:1:4
10:2:1
20:7:3
20:0:1
20:0:1
20:0:1
20:0:1
(9) It has been shown that high pressures of CO impedes the overall
carbonylative reaction. See: (a) Barnard, C. F. J. Org. Process Res. Dev.
2008, 12, 566. (b) Kormos, C. M.; Leadbeater, N. E. Synlett 2007, 13,
[(cinnamyl)PdCl]2
82
[(cinnamyl)PdCl]2 P(o-tol)3 (5.0)
[(cinnamyl)PdCl]2 P(o-tol)3 (2.5)
[(cinnamyl)PdCl]2 cataCXium A (2.5)
[(cinnamyl)PdCl]2 PPh3 (2.5)
93
~
ꢀ
2006. (c) Gavino, R.; Pellegrini, S.; Castanet, Y.; Mortreux, A.; Mentre,
>95
85
O. Appl. Catal., A 2001, 217, 91.
(10) Sergeev, A. G.; Spannenberg, A.; Beller, M. J. Am. Chem. Soc.
2008, 130, 15549.
(11) Alternatively, Hallberg and coworkers previously reported the
palladium catalyzed regioselective β-aroylation of vinyl ethers using
aroyl chlorides. See: Anderson, C.-M.; Hallberg, A. J. Org. Chem. 1988,
53, 4257.
(12) Hermange, P.; Gøgsig, T. M.; Lindhardt, A. T.; Taaning, R. H.;
Skrydstrup, T. Org. Lett. 2011, 13, 2444.
(13) For the direct synthesis of 1,3-diketones starting from aryl
iodides, see: Gøgsig, T. M.; Taaning, R. H.; Lindhardt, A. T.; Skrydstrup,
T. Angew. Chem., Int. Ed. 2012, 51, 798.
(14) Hermange, P.; Lindhardt, A. T.; Taaning, R. H.; Bjerglund, K.;
Lupp, D.; Skrydstrup, T. J. Am. Chem. Soc. 2011, 133, 6061.
(15) COware and COgen are commercially available at sytracks.com.
>95
90
10 [(cinnamyl)PdCl]2 P(Ph)2Bn (2.5)
11 [(cinnamyl)PdCl]2 X-Phos (2.5)
92
12 [(cinnamyl)PdCl]2 HBF4P(t-Bu)3 (2.5)
13 [(cinnamyl)PdCl]2c HBF4P(t-Bu)3 (2.5)
14d [(cinnamyl)PdCl]2 HBF4P(t-Bu)3 (2.5)
15e,f [(cinnamyl)PdCl]2 HBF4P(t-Bu)3 (2.5)
>95
69
88
>95
a Chamber A: 1 (0.45 mmol), Pd(dba)2 (5 mol %), HBF4P(t-Bu)3
(5 mol %), DIPEA (0.68 mmol) in dioxane (2 mL). Chamber B: 4-
Iodotoluene (0.3 mmol), butyl vinyl ether (1.8 mmol), Cy2NMe (0.9 mmol),
ligand (5 mol %), [Pd] (5 mol %) in dioxane (2 mL). b Isolated yield. c [Pd]
(1.25 mol %). d Reaction run at 90 °C. e In Chamber A: 1 (0.66 mmol).
f In Chamber A: Pd(dba)2 (1 mol %), HBF4P(t-Bu)3 (1 mol %).
€
(16) (a) Gurtler, C.; Buchwald, S. L. Chem.;Eur. J. 1999, 5, 3107.
(b) Hills, I. D.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 13178.
(17) Gottumukkala, A. L.; de Vries, J. G.; Minnaard, A. J. Chem.;
Eur. J. 2011, 17, 3091.
Org. Lett., Vol. 14, No. 10, 2012
2537

Improved selectivity and comparable catalytic activity
were observed when employing [(cinnamyl)PdCl]2 as the
catalyst precursor (entry 5). The addition of monodentate
phosphine based ligands lowered the amount of reduced
product, and the desired R,β-unsaturated ketoether was
produced nearly exclusively when HBF4(t-Bu)3 was ap-
plied to the carbonylative β-arylation (entry 12).18 The
formation of a neutral tricoordinated T-shaped complex
subsequent to the oxidative addition, securing the catalytic
cycle to be operated by a neutral mechanism, could
possibly explain the regioselective outcome of the
reaction.19 Interestingly, P(t-Bu)3 proved ineffective in
the carbonylative Heck reaction of styrenes neglecting
the incorporation of carbon monoxide and providing the
stilbene products.12 On the other hand cataCXium A
proved less effective promoting the direct R-arylated Heck
product to a higher extent (entry 8). Importantly, a 2:1
ratio of the Pd precursor and the phosphine ligand proved
mandatory in order to generate an efficient catalytic
system (entries 6, 7, and 13). This effect corresponds with
the kinetic data published by Heck and co-workers ob-
tainedon the basisof 13discrete complexes, demonstrating
that the addition of excess phosphine impeded the rate of
carbon monoxide insertion.20 This can be overcome by
increasing the CO pressure, which in turn may require
higher phosphine loadings as earlier described. Lowering
the reaction temperature obstructed the catalytic turnover
(entry 14). Finally, optimal reaction conditions were ob-
tained when applying 2.2 equiv of carbon monoxide to
the reaction mixture resulting in the monoprotected aryl
ketoaldehyde in an 81% isolated yield (entry 15).
Noteworthy, a catalyst loading of 1 mol % in Chamber
A proved equally suitable for an efficient CO release
(entry 15).
Scheme 1. Scope of the Carbonylative Heck Reactiona,b
a Chamber A: 1 (1.10 mmol), Pd(dba)2 (1 mol %), HBF4P(t-Bu)3
(1 mol %), DIPEA (1.65 mmol) in dioxane (3 mL). Chamber B: Aryl
iodide (0.50 mmol), butyl vinyl ether (3.0 mmol), Cy2NMe (1.50 mmol),
HBF4P(t-Bu)3 (2.5 mol %), [(cinnamyl)PdCl]2 (2.5 mol %), dioxane
b Isolated yields are given.
(4 mL) for 17 h.
optimized conditions resulting in trace amounts of the
desired products (results not shown).
These results prompted us to explore the scope of the
carbonylative β-arylation testing different aryl iodides. As
depicted in Scheme 1 a wide variety of aryl iodides under-
went a successful coupling using the optimized reaction
conditions.
Having established an efficient strategy for the direct
synthesis of 1,3-ketoaldehyde surrogates, the applicability
of these structures was studied (Scheme 2). Heterocyclic
moieties such as pyrazole, isoxazole, and pyrimidine
based structures were easily obtained treating the re-
sulting keto vinyl ethers with the appropriate nucleo-
phile. As an example, the 2,4-disubstituted pyrimidine
24 was assembled in an 83% yield starting from the
monoprotected ketoaldehyde and benzamidine under
basic conditions at 50 °C. Furthermore, hydrazine and
hydroxylamine proved equally effective producing the
pyrazole 23 and isoxazole 25 derivatives, respectively,
in excellent yields.
Aryl iodides displaying both electron-donating and -
withdrawing groups provided the β-aroylated vinyl ethers
effectively. Arenes carrying ester, cyano, silylether, sulfide,
trifluoromethyl, carbamate, and amino groups coupled
smoothly complementing the exceptional functional group
tolerance typically observed in the Heck reaction (7À9 and
11À16). Protected catecholes and indoles also proved
suitable and good yields could be secured after column
chromatography (18 and 19). The presence of chloride and
fluoride did not seem to influence the outcome of the
carbonylative Heck reaction (20 and 21). On the other
hand, activation of the bromide could potentially account
for the moderate yield obtained employing 3-bromoiodo-
benzene (22). Aryl bromides proved less effective under the
The stoichiometric amounts of applied carbon monox-
ide allowed ustoinvestigate the 13C-isotopelabeling of aryl
methyl ketones obtained by hydrolysis of the initially
formed keto vinyl ether with aqueous hydrogen chloride
(Scheme 3).
This protocol represents a direct synthesis of carbon
isotope labeled acetophenone derivatives and comple-
ments the synthesis of acetylated benzene derivatives
obtained by the Heck reaction of aryl electrophiles and
vinyl ethers using only a slight excess of 13C-labeled carbon
(18) A range of bidentate ligands were tested including DPPF,
Xantphos, (()BINAP, and PPF-t-Bu proved inferior generating sig-
nificant amounts of the direct R-arylated vinyl ether.
(19) Barrios-Landeros, F.; Carrow, B. P.; Hartwig, J. F. J. Am.
Chem. Soc. 2009, 131, 8141.
(20) Garrou, P. E.; Heck, R. F. J. Am. Chem. Soc. 1976, 98, 4115.
2538
Org. Lett., Vol. 14, No. 10, 2012

Scheme 2. Heterocyclic Compounds Obtained from a
1,3-Ketoaldehyde Synthon
Scheme 3. 13C-Labeled Aryl Methyl Ketones Obtained from
1,3-Ketoaldehyde Synthonsa,b
a For reaction procedures, see Supporting Information. bOverall
yields are given. cObtained in one pot.
Further investigations into this effect are en route and will
be reported in due time.
monoxide. For instance, 13C-labeled 4-methoxyacetophe-
none 26 was successfully produced in a 73% isolated yield
illustrating the diversity and utility of Pd-catalyzed carbo-
nylative chemistry when limited amounts of carbon mon-
oxide are employed.
In conclusion, a simple approach for the synthesis of 1,3-
ketoaldehyde synthons has been found starting from aryl
iodides employing a palladium catalyst and near stoichio-
metric amounts of carbon monoxide. The monoprotected
1,3-ketoaldehydes were obtained with complete regioselec-
tivity. This suggests that the formation of the intermediary
aroylpalladium complex dictates the regioselective out-
come of the reaction affording the linear products, when
electron-rich olefins such as vinyl ethers are applied.
Acknowledgment. We are deeply appreciative of the
generous financial support from the Danish National
Research Foundation, the Carlsberg Foundation, the
Lundbeck Foundation, the Danish Natural Science Re-
search Council, and Aarhus University.
Supporting Information Available. Experimental de-
tails and copies of the 1H and 13C NMR spectra for all the
coupling products. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 10, 2012
2539