Carbonylative heck reactions using CO generated ex situ in a two-chamber System

Article abstract of DOI:10.1021/ol200686h

Chemical equations presented. A carbonylative Heck reaction of aryl iodides and styrene derivatives employing a two-chamber system using a stable, crystalline, and nontransition metal based carbon monoxide source is reported. By applying near-stoichiometr

Full text of DOI:10.1021/ol200686h

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2444–2447
Carbonylative Heck Reactions Using CO
Generated ex Situ in a Two-Chamber
System
Philippe Hermange, Thomas M. Gøgsig, Anders T. Lindhardt, Rolf H. Taaning, and
Troels Skrydstrup*
Center for Insoluble Protein Structures (inSPIN), Department of Chemistry and
the Interdisciplinary Nanoscience Center, Aarhus University, Langelandsgade 140,
8000 Aarhus C, Denmark
ts@chem.au.dk
Received March 15, 2011
ABSTRACT
A carbonylative Heck reaction of aryl iodides and styrene derivatives employing a two-chamber system using a stable, crystalline, and
nontransition metal based carbon monoxide source is reported. By applying near-stoichiometric amounts of the carbon monoxide precursor, an
effective exploitation of the hazardous CO gas is obtained affording chalcone derivatives in good yields. Application to isotope labeling,
incorporating 13CO, was further established.
Since its discovery in 1968, the Heck reaction has proved
itself to be one of the most useful palladium catalyzed
reactions for CÀC bond formation.1 Due to the impressive
functional group tolerance and vast applications, the Heck
reaction has recently been decorated with the Nobel Prize
together with the Suzuki and Negishi cross couplings.
Nevertheless, improvements, new variations, and mechan-
istic insights are reported on a regular basis further illus-
trating the importance of this reaction.2
To make catalysis even more efficient and diverse, focus
has been aimed on the introduction of multiple compo-
nents to catalytic processes forming several bonds in a one-
step procedure.3 In particular, the direct incorporation of
carbon monoxide as a one carbon fragment into the
established palladium catalyzed reactions has received
much attention. The resulting carbonylated product often
acts as an entry point to further manipulations or serves as
a valuable motif in itself. These transformations include
amino-, thio-, and alkoxycarbonylations, carbonylative
Suzuki and Sonogashira reactions, formylations, and car-
boxamidations to address a few.4
(1) (a) Hartwig, J. F. In Organotransition Metal Chemistry: From
Bonding to Catalysis; University Science Books: 2010. (b) Heck, R. F.
J. Am. Chem. Soc. 1968, 90, 5538. (c) Mizoroki, T.; Mori, K.; Ozaki, A.
Bull. Chem. Soc. Jpn. 1971, 44, 581. (d) Heck, R. F.; Nolley, J. P., Jr.
J. Org. Chem. 1972, 37, 2320. (e) Dieck, H. A.; Heck, R. F. J. Am. Chem.
Soc. 1974, 96, 1133.
(2) (a) Carrow, B. P.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 79.
(b) Henriksen, S. T.; Norrby, P.-O.; Kaukoranta, P.; Andersson, P. G.
J. Am. Chem. Soc. 2008, 130, 10414. (c) Ebran, J.-P.; Hansen, A. L.;
Gøgsig, T. M.; Skrydstrup, T. J. Am. Chem. Soc. 2007, 127, 6931. (d)
Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989. (e) Mo, J.; Xu,
L.; Xiao, J. J. Am. Chem. Soc. 2005, 127, 751. (f) Hansen, A. L.; Ebran,
J.-P.; Ahlquist, M.; Norrby, P.-O.; Skrydstrup, T. Angew. Chem., Int.
Ed. 2006, 45, 3349.
(3) (a) Siamaki, A. R.; Arndtsen, B. A. J. Am. Chem. Soc. 2006, 128,
~
ꢀ
6050. (b) Barluenga, J.; Mendoza, A.; Rodrıguez, F.; Fananas, F. J.
Angew. Chem., Int. Ed. 2009, 48, 1644. (c) Oisaki, K.; Zhao, D.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 7439.
€
(4) (a) For review, see: Brennfuhrer, A.; Neumann, H.; Beller, M.
Angew. Chem., Int. Ed. 2009, 48, 4114 and references herein. (b)
Munday, R. H.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc.
2008, 130, 2754. (c) Wu, X.-F.; Neumann, H.; Beller, M. Chem.;Eur. J.
2010, 16, 9750.
r
10.1021/ol200686h
Published on Web 04/06/2011
2011 American Chemical Society

On the other hand, intermolecular carbonylative Heck
couplings, introduced by Miura and co-workers in 1995,
have been described to a lesser extent.5,6 Recently, Beller
and co-workers expanded this process disclosing a general
strategy for the synthesis of pharmaceutical attractive
chalcone related compounds starting from aryl halides in
combination with carbon monoxide and acyclic olefins.
Relatively high pressures (5À10 bar) of CO ensured by the
use of an autoclave and a specially designed ligand proved
mandatory.7 The handling of high pressure carbon mon-
oxide, being a flammable, toxic, and teratogenic gas,
requires specific safety precautions hereby limiting its
applicability in both industry and academia.
ligand P(tBu)3 together with N-diisopropyl-N-ethylamine
(DIPEA) as base proved effective (Scheme 1, A).8c,9,10
Preliminary investigations revealed PdCl2 as a promis-
ing catalyst for the carbonylative Heck coupling of 4-io-
doanisole and styrene in the presence of N,N-dicyclo-
hexylmethylamine (Cy2NMe) in dioxane using a slight
excess of carbon monoxide (Table 1, entry 1). Noteworthy,
no ligand was needed for completion of the reaction, but
unfortunately substantial amounts of the reduced chal-
cone were detected.11 Changing the catalyst to [(cinnamyl)
PdCl]2 gave a homogeneous reaction mixture, but similar
conversions and ratios of the desired and reduced product
were obtained.
Table 1. Optimization of the Carbonylative Heck Reaction in
the Two-Chamber Systema
Scheme 1. Ex Situ CO Generation from the Two-Chamber
System
conversion [%]b
ratio
(isolated
entry
[Pd]
ligand
2:3
yield) [%]
1
PdCl2
-
-
-
-
4:1
7:2
4:1
4:1
5:1
3:1
0:0
>95
94
As illustrated in Scheme 1 we wish to report on a newly
developed two-chamber system enabling a measured
amount of CO, generated ex situ from a stable, crystalline,
and nontransition metal based CO source (Chamber A), to
be consumed in a parallel carbonylative Heck reaction
(Chamber B). Furthermore, the unique setup unlocks a
new efficient technique for carbon isotope labeling with
mild reaction conditions.8
Based on previous work done by our group, an
R-quaternary substituted acid chloride with the capability
to undergo decarbonylation and subsequent β-hydride
elimination when subjected to an appropriate palladium
complex was chosen as the CO source (see Supporting
Information).
2
Pd(OAc)2
3
[(allyl)PdCl]2
[(cinnamyl)PdCl]2
>95
>95 (82)
62
4
5c
6c
[(cinnamyl)PdCl]2 PPh3
[(cinnamyl)PdCl]2 PCy3HBF4
38
7c,d [(cinnamyl)PdCl]2 P(t-Bu)3
>95
51
8c
[(cinnamyl)PdCl]2 cataCXium A >95:5
[(cinnamyl)PdCl]2 cataCXium A >95:5
[(cinnamyl)PdCl]2 cataCXium A >95:5
9e
90
10f
>95 (74)
>95
11g [(cinnamyl)PdCl]2 cataCXium A 95:5
a Chamber A: 1 (0.75 mmol), Pd(dba)2 (1 mol %), P(t-Bu)3 (1 mol %),
DIPEA (0.75 mmol) in dioxane (3 mL) for 20 h. Chamber B: Iodoani-
sole (0.5 mmol), styrene (3.0 mmol), Cy2NMe (1.5 mmol), [Pd] (5 mol %) in
dioxane (3 mL) for 20 h. b Determined by 1H NMR analysis. c Ligand
(7.5 mol %). d Only the direct Heck coupling product was observed.
e Ligand (2.5 mol %). f Ligand (1 mol %). g Ligand (0.5 mol %).
In this regard, 9-methyl-fluorene-9-carbonyl chloride 1
in combination with Pd(dba)2 and the sterical encumbered
Addition of a phosphine ligand at 7.5 mol % such as
PPh3, PCy3, P(tBu)3, and cataCXium A influenced both
the conversions and ratios (Table 1, entries 5À8). With
P(tBu)3 only direct coupling and the formation of stilbene
were surprisingly observed.12,13 On the other hand, em-
ploying cataCXium A resulted in excellent selectivity
(5) Satoh, T.; Itaya, T.; Okuro, K.; Miura, M.; Nomura, M. J. Org.
Chem. 1995, 60, 7267.
(6) For intramolecular Heck reactions, see: (a) Gagnier, S. V.; Larock,
R. C. J. Am. Chem. Soc. 2003, 125, 4804. (b) Wu, X.; Nilsson, P.; Larhed,
M. J. Org. Chem. 2005, 70, 346.
(7) (a) Wu, X.-F.; Neumann, H.; Spannenberg, A.; Schulz, T.; Jiao,
H.; Beller, M. J. Am. Chem. Soc. 2010, 132, 14596. (b) For aryl triflates,
see: Wu, X.-F.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 201049,
5284. (c) For DFT computations, see: Wu, X.-F.; Jiao, H.; Neumann, H.;
Beller, M. ChemCatChem 2011, 3, 726.
(9) Gauthier, D.; Lindhardt, A. T.; Olsen, E. P. K.; Overgaard, J.;
Skrydstrup, T. J. Am. Chem. Soc. 2010, 132, 7998.
(10) The air- and moisture-stable HBF4P(tBu)3 salt performed
equally well.
(11) Ether based solvents or trialkylamines are known to act as
reducing agents: (a) Martins, A.; Candito, D. A.; Lautens, M. Org.
(8) (a) For carbonylation reactions using Mo(CO)6, and Co2(CO)8,
see: Wannberg, J.; Larhed, M. In Modern Carbonylation Methods;
ꢀ
Kollar, L., Ed.; Wiley-VCH: 2008; pp 93À112. (b) For carbonylation
reactions using Wo(CO)6, see: Wie-ckowska, A.; Fransson, R.; Odell,
L. R.; Larhed, M. J. Org. Chem. 2011, 76, 978. (c) Hermange, P.;
Lindhardt, A. T.; Taaning, R. H.; Bjerglund, K.; Lupp, D.; Skrydstrup,
T. J. Am. Chem. Soc. 2011ASAP (DOI: 10.1021/ja200818w). (d) Patent
application currently proceeding: Taaning, R. H.; Hermange P.; Lindhardt,
A. T.; Skrydstrup, T. (Aarhus University, DK) System providing controlled
delivery of gaseous CO for carbonylation reactions. PA 2010 70546,
December 15, 2010.
ꢀ
Lett. 2010, 12, 5186. (b) Coquerel, Y.; Bremond, P.; Rodriguez, J.
J. Organomet. Chem. 2007, 692, 4805.
(12) A similar effect was noted by the group of Beller in the formyla-
tion of aryl halides; see ref 8 and: Klaus, S.; Neumann, H.; Zapf, A.;
€
€
Strubing, D.; Hubner, S.; Almena, J.; Riermeier, T.; Gross, P.; Sarich,
M.; Krahnert, W.-R.; Rossen, K.; Beller, M. Angew. Chem., Int. Ed.
2006, 45, 154.
Org. Lett., Vol. 13, No. 9, 2011
2445

generating the R,β-unsaturated ketone exclusively (Table 1,
entry 8).14 Under the assumption that excess ligand de-
creased the amount of the catalytically active species, the
Pd/phosphine ratio was next investigated using this ligand
(Table 1, entries 9À11). We were pleased to see that
reducing the amount of cataCXium A to 1 mol % restored
full conversion while maintaining an excellent selectivity,
and a 74% yield of 2 could be secured upon column
chromatography (Table 1, entry 10). In contrast, decreasing
both palladium and phosphine loadings resulted in a detri-
mental effect (See Supporting Information).
to be the most effective in facilitating CO incorporation
and good yields were secured (entries 1À6).8,15 Further-
more, heterocyclic compounds were well tolerated, and
perfect chemoselectivities are attained in the coupling of
4-bromoiodobenzene allowing further functionalization
(entries 6, 7, 10). Ortho-substituents and electron-with-
drawing groups lowered the outcome of the carbonylative
reaction, and increased amounts of the stilbene derivative
were observed (entries 8, 11).15
Scheme 2. Scope of the Carbonylative Heck Reaction in the
Two-Chamber Systema
Table 2. Scope of the Carbonylative Heck Reaction in the
Two-Chamber System
a Conditions i: Chamber A: 1 (0.75 mmol), Pd(dba)2 (1 mol %),
P(t-Bu)3 (1 mol %), DIPEA (0.75 mmol) in dioxane (3 mL) for 20 h.
Chamber B: Iodoanisole (0.5 mmol), olefin (3.0 mmol), Cy2NMe
(1.5 mmol), cataCXium A (1 mol %), [(cinnamyl)PdCl]2 (2.5 mol %)
in dioxane (3 mL) for 20 h. Conditions ii: Same as i using olefin (1 mmol)
for 40 h in Chamber B.
Carbonylative vinylation of 4-iodoanisole exploiting
different styrene derivatives was then studied using the
described reaction conditions (Scheme 2). Alternatively,
only 2 equiv of the olefin and prolonged reaction times
could successfully be applied obtaining comparable yields.
Gratifyingly, various substituted styrenes coupled effec-
tively to 4-iodoanisole employing the two-chamber system
forming the corresponding carbonylated stilbene in good
yields. Both electron-rich and -deficient styrenes per-
formed well using only a small excess of carbon monoxide.
Again, ortho-substituents on the aryl iodide lowered the
yield. However, an acceptable 42% isolated yield of the
diuretic metochalcone 21 was accomplished, also being a
precursor to a flavone derived compound.16
a Chamber A: 1 (0.75 mmol), Pd(dba)2 (1 mol %), P(t-Bu)3 (1 mol %),
DIPEA (0.75 mmol) in dioxane (3 mL) for 20 h. Chamber B: Iodoanisole
(0.5 mmol), styrene (3.0 mmol), Cy2NMe (1.5 mmol), cataCXium A
(1 mol %), [(cinnamyl)PdCl]2 (2.5 mol %) in dioxane (3 mL) for 20 h.
b Isolated by flash column chromatography.
Next, the scope of the two-chamber carbonylative Heck
reaction using only 1.5 equiv of carbon monoxide was
tested (Table 2). In general, moderate to good yields of the
desired chalcone derivatives were obtained. In accordance
withtheliterature, electron-richarenesrevealedthemselves
(13) Low incorporation of CO in the carbonylative Heck reaction
was reported by the group of Beller using P(tBu)3. The higher CO
pressure employed could potentially acount for this observation; see
ref 7a.
(14) Sergeev, A. G.; Spannenberg, A.; Beller, M. J. Am. Chem. Soc.
2008, 130, 15549.
(15) Studies on the electronic properties of organopalladium com-
plexes affecting the CO capture have been described revealing electron-
donating groups to enhance the CO incorporation. See: (a) Garrou,
P. E.; Heck, R. F. J. Am. Chem. Soc. 1976, 98, 4115. (b) Ishiyama, T.;
Kizaki, H.; Hayashi, T.; Suzuki, A.; Miyaura, N. J. Org. Chem. 1998, 63,
4726.
2446
Org. Lett., Vol. 13, No. 9, 2011

amounts. To our delight, the two-chamber system
proved effective facilitating the 13C insertion, employ-
ing the described conditions (Scheme 3). The 13C
labeled chalcone *19 and [13C]metochalcone *21 were
secured in good yields based on the carbon mono-
xide precursor. Additionally, 13CO was smoothly
assimilated into an indanone scaffold *23 in a two-
step procedure starting from 3,4,5-trimethoxyiodo-
benzene.
Scheme 3. Isotope Labeling Using the Two-Chamber System
In conclusion, carbonylative Heck reactions of various
aryl iodides and styrene derivatives using only slight excess
ofcarbonmonoxide ina two-chambersystemarereported.
The described method demonstrates it to be a powerful
tool for the isotope labeling of chalcone derived com-
pounds. This technology opens a new method for carbo-
nylative isotope chemistry, and further applications are en
route in our laboratories.
Acknowledgment. We are deeply appreciative of the
generous financial support from the Danish National
Research Foundation, the Danish Natural Science Re-
search Council, and Aarhus University.
Finally, we decided to test the two-chamber system
in 13C isotope labeling. 9-Methyl-fluorene-9-[13C]
carbonyl chloride *1, readily obtained from 9-fluore-
none, was utilized as the 13CO source in substoichiometric
Supporting Information Available. Experimental de-
1
tails and copies of H and 13C NMR spectra for all the
coupling products. This material is available free of
charge via the Internet at http://pubs.acs.org.
(16) Yao, N.; Song, A.; Wang, X.; Dixon, S.; Lam, K. S. J. Comb.
Chem. 2007, 9, 668.
Org. Lett., Vol. 13, No. 9, 2011
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