Palladium(II)-catalyzed decarboxylative heck arylations of acyclic electron-rich olefins with internal selectivity

Article abstract of DOI:10.1002/adsc.201301004

Despite the recent emergence of decarboxylative C-C bond forming reactions, methodologies providing internally arylated electron-rich olefins are still lacking. We herein report on palladium(II)-catalyzed decarboxylative Heck arylations of linear electron-rich olefins with excellent selectivity for the internal position. The method allows a variety of electron-rich linear olefins to undergo arylation with ortho-functionalized aromatic carboxylic acids, including heterocycles. The reaction mechanism has been explored with ESI-MS studies to confirm previous findings, and to reveal the formation of a highly stable palladium complex as a result of the Heck product reacting with the catalyst.

Full text of DOI:10.1002/adsc.201301004

UPDATES
DOI: 10.1002/adsc.201301004
Palladium(II)-Catalyzed Decarboxylative Heck Arylations of
Acyclic Electron-Rich Olefins with Internal Selectivity
Ashkan Fardost,a Jonas Lindh,a Per J. R. Sjçberg,b and Mats Larheda,*
a
Division of Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Centre,
Uppsala University, Husargatan 3, 75123, Uppsala, Sweden
E-mail: mats.larhed@orgfarm.uu.se
Department of Chemistry, Uppsala Biomedical Centre, Uppsala University, Husargatan 3, 75123, Uppsala, Sweden
b
Received: November 11, 2013; Published online: March 3, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201301004.
Abstract: Despite the recent emergence of decar-
boxylative C C bond forming reactions, methodolo-
gies providing internally arylated electron-rich ole-
fins are still lacking. We herein report on palladi-
ACHTUNGTRENNUNGum(II)-catalyzed decarboxylative Heck arylations
of linear electron-rich olefins with excellent selec-
tivity for the internal position. The method allows
a variety of electron-rich linear olefins to undergo
arylation with ortho-functionalized aromatic car-
boxylic acids, including heterocycles. The reaction
mechanism has been explored with ESI-MS studies
to confirm previous findings, and to reveal the for-
mation of a highly stable palladium complex as
a result of the Heck product reacting with the cata-
lyst.
ments of both the classical Mizoroki–Heck reaction
and its oxidative counterpart have provided for an im-
pressive array of aryl-palladium precursors and olefin-
ic substrates,[6,15,16] but there are shortcomings that jus-
tify further development. These include environmen-
tal hazards of aryl halides and their by-products, and
limited commercial availability, laborious preparation,
high cost and instability of some organometallic sub-
strates.[6,15,16]
À
Metal-mediated decarboxylations of carboxylic
acids were discovered in 1930,[17] and incremental de-
velopments followed,[18–24] but they were not exploited
À
for C C bond formations until recently. Pioneering
work by Myers et al. showed that certain benzoic
acids can undergo a palladium(II)-catalyzed process
in which carbon dioxide is released to form the corre-
sponding aryl-palladium complex, which in the pres-
ence of an oxidant (Ag2CO3) and alkenes yields vinyl-
arenes.[25] As carboxylic acids are cheap, non-toxic,
easy to prepare and widely available, the aforemen-
tioned drawbacks of traditional aryl-palladium precur-
sors may thus be countered.[26,27] One major drawback
of using palladium(II) catalysts for decarboxylation is
Keywords: carboxylic acids; Heck reaction; mass
spectrometry; olefination; palladium; reaction
mechanisms
The Heck reaction and its spin-offs continue to serve the limitation to ortho-substituent bearing benzoic
chemists as a vital tool for the formation of C C acids,[28–30] although Gooßen and co-workers have ex-
À
bonds between olefins and arenes.[1–9] While Mizoro- panded the scope beyond this limitation for some
ki[1] and Heck[2] independently pioneered the palladi- non-oxidative cross-coupling reactions by employing
um(0)-catalyzed arylation of an alkene with an organ- bimetallic systems.[31–33] Several applications of palla-
ic halide, today known as the “classic Mizoroki–Heck dium(II)-catalyzed decarboxylations have now been
reaction”, Heck would also discover in 1975 an analo- demonstrated, including Suzuki[34–36] and Sonoga-
gous palladium(II)-mediated vinylation of an olefin shira[37] cross-couplings, their oxidative counter-
by employing a vinylboronic acid and stoichiometric parts,[38,39] as well as oxidative Heck-type reac-
loadings of palladium acetate.[10] Although reoxidizing tions.[40–45] While successful efforts to promote internal
agents had been reported to allow palladium(II)-cata- selectivity in traditional Heck arylations of electron-
lyzed transformations already in 1968,[11] the so-called rich olefins are manifold,[46] and its decarboxylative
“oxidative Heck reactions” were not deemed feasible counterpart has been demonstrated for electron-rich
until Mori and co-workers demonstrated the use of cyclic olefins,[47] examples in the literature providing
CuACHTUNGTRENNUNG
(OAc)2 as a reoxidant of Pd(0) to Pd(II) in 2001,[12] access to internally arylated acyclic electron-rich ole-
followed by Jung and Larhed describing the use of fins via the decarboxylative pathway are lacking. Al-
molecular oxygen as a Pd(0) reoxidant.[13,14] Develop- though oxidative decarboxylative arylations of indoles
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Palladium(II)-Catalyzed Decarboxylative Heck Arylations
Table 1. Scope of aromatic carboxylic acids.[a]
[a]
[b]
[c]
[d]
1
Isolated yields. Regioselectivity confirmed by H NMR.
According to GC-MS.
Not detected by GC-MS.
Hydrolyzed and isolated as the corresponding ketone (see the Supporting Information).
have been demonstrated by Su and co-workers,[48] the carboxylic acid 1f. The heterocyclic 3-methylpyridine-
only acyclic electron-rich olefin example reported is carboxylic acid 1g was unable to produce 3g, again
a low-yielding reaction with no substrate variability.[49] likely due to sequestration of palladium by the pyri-
In 2010, our group reported a bidentate ligand- dine nitrogen. Interestingly, the 3-methylthiophene-
modulated palladium(II)-catalyzed decarboxylative carboxylic acid 1h furnished 3h in 39% yield while its
method for the addition of benzoic acids to nitriles, benzothiophene counterpart 1i only produced traces
promoting the formation of aryl ketones.[50,51] This in- of 3i. The benzofuran analogue 1j successfully reacted
spired us to investigate whether a similar catalytic to yield 41% of 3j, however. Despite the low to mod-
system might also promote decarboxylation and sub- erate range of yields, it is of crucial interest that all
sequent arylation of electron-rich olefins at the inter- successful reactions demonstrated excellent regiose-
nal position. Rewardingly, reacting 2,6-dimethoxyben- lectivity with no detection of the corresponding termi-
zoic acid (1a) with 1-vinylpyrrolidone (2a), using pal- nal regioisomer.
ladium(II) trifluoroacetate (PdTFA2) and 6-methyl-
The scope of olefinic substrates was explored by re-
2,2’-bipyridine (6-MBP) as the catalytic system and acting different terminal electron-rich olefins with 1a
para-benzoquinone (p-BQ) as the reoxidant and and the less electron-rich 1c (Table 2). The general
DMF as the solvent, furnished the desired Heck prod- pattern of reactivity was in agreement with previous
uct 3a in 77% isolated yield after 24 h at 1208C. Fur- studies,[29,30,41,52] namely that decreased electron densi-
thermore, no traces of terminally arylated Heck prod- ty in the aromatic ring resulted in reduced reactivity.
uct, 1a, or the protodecarboxylation by-product 1,3- Nevertheless, all product-yielding reactions provided
dimethoxybenzene could be detected by 1H NMR, arylation exclusively at the internal vinylic position.
GC-MS or LC-MS. To investigate the scope of the re- Alkyl vinyl ethers 2b and 2c and enamide 2f proved
action, a variety of ortho-substituted aromatic carbox- to be the most proactive olefinic substrates. While the
ylic acids was tested (Table 1).
outcome for N-vinylcaprolactam 2f was more or less
The di-ortho-substituted electron-rich carboxylic similar to that of enamide 2a, one would expect the
acids 1a and 1b provided the highest isolated yields outcomes for enamide 2d to be superior compared to
(77% and 68%), whereas the less electron-rich 2e. As the secondary amide nitrogen in 2e is expected
bromo-bearing aromatic acid 1c furnished a slightly to coordinate the catalyst more strongly than the ter-
lower yield of 3c (53%). The nitro- and amino-substi- tiary amide 2d, it is interesting that 4e was isolated in
tuted 1d and 1e yielded only traces of product, which a lower yield than 4g.
is likely due to a significant drop in electron density
As the reaction exhibited unanimous preference for
and coordination of the amino group to palladium, re- the internal position in the case of the electronically
spectively. The low yield of 3f was expected with re- biased olefins, we were interested in the behavior of
gards to the mono-ortho-substitution pattern of the a less electron-rich olefin. Thus, allyl alcohol was
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Ashkan Fardost et al.
Table 2. Scope of electron-rich olefins.[a]
[a]
1
Isolated yields. Regioselectivity confirmed by H NMR.
Hydrolyzed and isolated as the corresponding ketone (see the Supporting Information).
Not detected by GC-MS.
[b]
[c]
Scheme 1. Regioselectivity of allyl alcohol.
chosen for investigation (Scheme 1). A regioselectivi- with electron-poor olefins, we were interested in in-
ty of 17 to 1 was observed with allyl alcohol 2h in vestigating the cationic intermediates more in detail.
favor of the internal position (determined by Electrospray ionization mass spectroscopy (ESI-MS)
1H NMR) despite its electronically less biased nature, has been successfully utilized in the elucidation of key
which is in accordance with a cationic pathway in the intermediates in ongoing palladium-catalyzed trans-
catalytic cycle.[53] Interestingly, both regioisomers 4m formations due to its soft method of ionization which
and 4m’ were isolated as their corresponding saturat- yields few fragmentation products,[58–64] and was our
ed aldehydes. Although this in situ isomerization has tool of choice for further studies. The investigation
been reported,[54] and the factors controlling it investi- was carried out by setting up an array of 10 identical
gated,[55–57] high regioselectivities have only been ob- reactions, in which 1a reacted with 2a as described in
tained for the terminally arylated corresponding alde- Table 1, and then sampling them at 10 different reac-
hydes. Whether this process is the result of a palladi- tion times. Due to the build-up of pressure in the re-
um hydride reverse addition–elimination remains to action, setting up ten identical reaction vessels al-
be investigated, but the high regioselectivity for the lowed each vessel to be sampled once and then dis-
internally arylated product is noteworthy neverthe- carded. This eliminated the risk of interfering with
less.
the reaction due to a sudden drop in pressure, as op-
The mechanistic framework of oxidative decarboxy- posed to sampling the same reaction vessel 10 times.
lative Heck reactions was elucidated by Myers and After aliquots of each reaction were collected, an
co-workers in 2005, with kinetic data and experiments ESI-MS-(+) spectrum was recorded (within one hour
À
with the captured Ar Pd intermediate suggesting the after sampling) by scanning the last quadrupole (Q3)
extrusion of CO2 to be the rate-determining step.[52] of a QTrap instrument in linear ion trap mode. The
These findings have been supported by elaborate distributions of the detected organopalladium com-
DFT studies performed by Zhang et al.[30] As our cat- plexes (106Pd and 108Pd) at the 10 different reaction
alytic system employs a bidentate nitrogen-based times are depicted in Table 3, and their structures are
ligand and the olefin is electron-rich, in contrast to assigned based on MS/MS and given letters (A–D and
the monodentate system employed by Myers et al. 5) based on their plausible role in the catalytic cycle.
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Palladium(II)-Catalyzed Decarboxylative Heck Arylations
Table 3. Detected organopalladium complexes at different heating times.[a]
[a]
Gray shade intensity represents an approximation of relative abundance be-
tween the different complexes in the mother spectrum for each heating
time. Unidentified complexes omitted for clarity.
NN, Ar, R =as in Figure 1.
_
[b]
[c]
Heating time in minutes.
The highest prevalence of cationic organopalladium which likely preludes the aryl-insertion step, are also
complexes with the characteristic isotopic pattern of formed at room temperature; (iii) an unexpected
palladium were observed prior to heating (Table 3 ionic species 5 begins to form after 5 min of heating
and Figure 1), which is surprising since product for- and remains throughout the course of the reaction, in-
mation is not observable on GC-MS and LC-MS until dicating a highly stable complex that might present
at least 2 h of heating.
a dead end in the catalytic cycle. MS/MS for complex
While the structural natures of the detected and 5 revealed an aryl, olefin, palladium and ligand com-
identified complexes are consistent with previous ponent, but not enough information to deduce the
findings,[29,30,52,65] three observations are noteworthy: actual composition. In an attempt to isolate it, carbox-
(i) complex B, which precedes the decarboxylation ylic acid 1a and olefin 2a were reacted according to
step, is already formed at room temperature and di- Table 1 but with stoichiometric amounts of the palla-
minished within 5 min of heating, indicating a fast de- dium(II) catalyst instead of p-BQ and in a lower con-
carboxylation step which contradicts previous find- centration [to avoid formation and precipitation of
ings;[30,52] (ii) the decarboxylated aryl-palladium spe- Pd(0)], in order to obtain complex 5 in isolable
cies C and its olefin-coordinating counterpart D, amounts (Scheme 2). To our delight, complex 5 was
Figure 1. ESI-MS-(+) spectrum for the reaction of 1a with 2a as in Table 1 (prior to heating) with assigned Pd(II) com-
plexes.
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Ashkan Fardost et al.
Scheme 2. Reaction with stoichiometric loading of palladi-
ACHTUNGTRENNUNGum(II) at room temperature, according to LC-MS.
Scheme 3. Reaction of Heck product 3a and catalyst.
Figure 2. Proposed structure of complex 5 based on ESI-
MSn, HR-MS, 1H NMR, 13C NMR, HSQC, HMBC and
NOESY (left), and lowest energy conformation according to
DFT calculations (right) using Jaguar 7.9[68] employing the
B3LYP hybrid functional[69–71] and LACVP** basis set,
which uses an effective core potential for Pd and 6-31G**
detected on LC-MS as a discrete compound along
with Heck product 3a (see the Supporting Informa-
tion).
To establish if complex 5 is formed within the cata-
lytic cycle or outside the cycle with the Heck product,
3a was mixed with palladium and ligand in DMF
(Scheme 3). Surprisingly, LC-MS revealed the forma-
for elements H–Ar[72]
.
tion of 5 within 30 min of stirring at room tempera- cate that decarboxylation may be the rate-determin-
ture, with 3a still present in the solution. After 2 h of ing step after all, despite the ESI-MS experiments
stirring at room temperature, a slight increase in the suggesting otherwise: as catalytically active palladium
amount of complex 5 was observed according to LC- continuously decreases, the concentration of active
MS (Scheme 3), and the outcome remained un- species in the catalytic cycle must decrease likewise.
changed after a total of 24 h of stirring at room tem- Hence, it is not correct to assume that complex B and
perature. Heating of complex 5 to 1208C for 24 h did the decarboxylation product C rapidly diminish exclu-
not indicate decomposition or significant changes in sively as observed in the ESI-MS experiments
the ratio between 3a and 5. Addition of diethyl ether (Table 3), but rather that all organopalladium species
precipitated complex 5 to allow filtration and isola- in the catalytic cycle decrease in concentration below
tion, after which it was characterized experimentally the level of detection as palladacycle 5 accumulates to
(Figure 2, left). While fluorine was detected by dominate the ESI-mass spectra.
19F NMR and the TFA anion was detected on TOF-
Due to the similarities between olefin 2a and ole-
MS in negative mode, the expected TFA anion could fins 2d–f with regards to the enamide moiety, it
not be observed on 13C NMR, thus rendering the seemed plausible that their corresponding Heck prod-
anion of the complex currently uncharacterized. At- ucts are able to form homologues of complex 5. Thus,
tempts to obtain crystals for X-ray failed, despite Heck products 4e, 4g and 4i were reacted with stoi-
trying various crystallization methods and exchanging chiometric amounts of catalyst to indeed yield their
PdTFA2 to other palladium salts with anions such as corresponding homologous cationic species 6–8, the
ClÀ and BF4 . The experimental data were in accord- structures of which could be characterized experimen-
À
ance with the lowest energy conformation found for 5 tally (Scheme 4). No crystals could be obtained for
according to DFT calculations (Figure 2, right), how- metallacycles 6–8, nor could the expected TFA anion
ever. The nature of the transformation leading up to be detected on 13C NMR despite the presence of fluo-
palladacycle 5 is unknown, but it may be similar to rine on 19F NMR, but the lowest energy conforma-
[66,67]
À
À
C H activations of aromatic C H bonds.
tions found using DFT calculations were in this case
As structure 5 is formed from the Heck product also in accordance with the experimental data
and catalyst at room temperature (Scheme 3), it is (Figure 3). As for the true structures of 5–8 being
reasonable to assume that this also occurs during the formed in live decarboxylative Heck reactions, it is
decarboxylative Heck reaction. This means that the not unlikely for an equilibrium to be taking place be-
catalyst as well as Heck product 3a are consumed to tween positively charged and neutral complexes, with
form species 5, resulting in less catalytically active the intramolecular carbonyl oxygen or an external tri-
palladium being available for the Heck cycle thus re- fluoroacetate anion, as well as an aryl carboxylate
ducing both the efficiency of the catalytic cycle and anion, coordinating the palladium center interchange-
the yield of Heck product 3a. These findings also indi- ably. Performing the reaction with vinyl ether Heck
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UPDATES
Palladium(II)-Catalyzed Decarboxylative Heck Arylations
Scheme 4. Reactions of catalyst with Heck products from enamide-substituted olefins. Structures of 6–8 are based on ESI-
_
MSn, HR-MS, H NMR, 13C NMR, HSQC, HMBC, NOESY. NN, Ar, R =as in Figure 1.
1
Figure 3. Lowest energy conformations of complexes 6–8 according to DFT calculations (performed with the same parame-
ters as described in Figure 2).
product 4a, which lacks the enamide moiety, did not and MS/MS analyses of ongoing reactions detected
produce a corresponding palladium complex.
key intermediates in the catalytic cycle which con-
A plausible reaction route, derived from complexes firms previous findings regarding the mechanism. It
A–D and 5, is proposed in Scheme 5 and involves the was also found that the catalyst is intercepted by
following key steps: (i) carboxyl ligand exchange of some Heck products to form a highly stable complex
intermediate A with the carboxylic acid to form com- that presumably reduces both the yield and the effi-
plex B (which is in equilibrium with species B’ given ciency of the catalytic cycle. Ongoing efforts in our
the excess of olefin); (ii) decarboxylation of the palla- laboratory are aimed at expanding the scope of this
dium(II)-carboxylate to generate the aryl-palladium reaction, while providing further insight into the reac-
intermediate C; (iii) coordination of the olefin double tion mechanism by DFT calculations.
bond to give complex D; (iv) aryl-insertion followed
by internal rotation to produce structure E; (v) b-hy-
dride elimination and release of product to form com-
plex F; (vi) reoxidation of Pd(0) to Pd(II) by p-BQ to
Experimental Section
generate bidentate coordinated catalyst A which
either reinitiates the catalytic cycle, or (vii) in the case
of olefins 2a and 2d–f undergoes a reaction with their
corresponding Heck products to yield 5–8, respective-
General Information
Reactions were performed in Teflon-coated stir-bar-contain-
ing Biotage 2–5 mL process vials. Analytical TLC was per-
formed using Merck aluminium-backed 0.2 mm silica gel 60
ly.
F-254 plates. Visualization was done with UV light. Silica
In conclusion, we have developed an oxidative pal-
gel 60 was purchased from Merck. Aluminum oxide (activat-
ed, neutral, Brockmann I, STD grade, approx. 150 mesh,
ladium(II)-catalyzed Heck method that gives access
to internally arylated electron-rich olefins with excel-
58 ꢁ) was purchased from Sigma–Aldrich. NMR spectra
lent regioselectivity, compatible with a wide variety of
1
were recorded on a Varian Mercury plus at 258C for H at
400 MHz, for 13C NMR at 100 MHz. Chemical shifts (d) are
linear electron-rich olefins and various ortho-function-
alized benzoic acids, including heterocycles. ESI-MS reported in ppm and referenced indirectly to TMS via the
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Ashkan Fardost et al.
Scheme 5. Proposed reaction route supported by MS-detected organopalladium complexes.
solvent (or residual solvent) signals. Low-resolution mass
spectra were recorded on a GC-MS instrument equipped
with a CP-Sil 8 CB capillary column (30 mꢂ0.25 mm,
0.25 mm) operating at an ionization energy of 70 eV. The
oven temperature (GC) was 70–3008C. Analytical UHPLC-
MS was performed on a Dionex UltiMate 3000 with
a Bruker amaZon iontrap mass spectrometer using a Phe-
nomenex Kinetex core-shell C18, 2.6 mm, 4.6ꢂ50 mm
column with MeCN in 0.05% aqueous HCOOH as mobile
phase at a flow rate of 2 mLminÀ1. All solvents, starting ma-
terials, and reagents are commercially available and were
used as received.
ACHTUNGTERNtNUNG ate:Et3N) to furnish the product 3a as a pale green oil;
yield 190 mg (77%); 1H NMR (400 MHz, CDCl3): d=7.22
(t, J=8.5 Hz, 1H), 6.54 (d, J=8.5 Hz, 2H), 5.67 (s, 1H),
4.81 (s, 1H), 3.77 (s, 6H), 3.36 (t, J=7.0 Hz, 2H), 2.43 (t,
J=8.0 Hz, 2H), 1.99–1.86 (m, 2H); 13C NMR (100 MHz,
CDCl3): d=173.86, 158.11, 135.62, 129.55, 115.45, 106.41,
103.87, 56.04, 48.33, 32.59, 17.89; HR-MS (ESI+):: m/z=
248.1284, calcd. for C14H17NO3 [M+H]+: 248.1287.
Procedure for ESI-MS-(+) Experiments
This study used a 3200 QTrap mass spectrometer manufac-
tured by AB Sciex (Concord, ON, Canada). A 100 mL ali-
quot was collected from each reaction mixture, diluted 10
times with acetonitrile, and introduced by continuous infu-
sion with the aid of a syringe pump at a flow-rate of
5 mLminÀ1 through a fused silica capillary (with a 50 mm
inner and a 184 mm outer diameter). The ion source used
was a Turbo V source in positive ESI mode. The following
MS conditions were used: temperature (TEM) ambient, cur-
tain gas (CUR) 15 psi, ion source gas 1 (GS1) 10 psi, ion
source gas 2 (GS2) 10 psi, ion spray voltage (IS) 5500 V, the
declustering potential (DP) was 40 V and entrance potential
(EP) 10 V for all measurements. MS data were collected in
enhanced MS mode (EMS) and MS/MS data were collected
in enhanced product ion mode (EPI). The collision gas pa-
rameter (CAD) was set to an arbitrary number, 11, for EMS
(linear ion trap MS scan) and high for the EPI, which corre-
sponds to a pressure reading of 4.0ꢂ10À5 Torr. The collision
energy (CE) was 25 eV for all experiments aside from the
EMS where it was set to 10 eV. Acquisition and processing
of the MS data was performed with Analyst 1.4.2 (AB
Sciex).
General Procedure for Decarboxylative Heck
Arylations (Table 1 and 2) Exemplified in the
Synthesis of 3a
A 2–5 mL process vial was charged with 2,6-dimethoxyben-
zoic acid 1a (182 mg, 1 mmol), 1-vinylpyrrolidine-2-one
(111 mg, 2 mmol), PdACHTUNRGTNE(UGN O2CCF3)2 (6.7 mg, 0.02 mmol), 6-
methyl-2,2’-bipyridine (4.1 mg, 0.024 mmol), para-benzoqui-
none (130 mg, 1.2 mmol) and DMF (2 mL). The vial was
thereafter capped under air and heated in a metal block pre-
heated to 1208C for 24 h. The reaction mixture was cooled
to room temperature, diluted with ethyl acetate (5 mL) and
filtered through an aluminum oxide plug using a 78:20:2
mixture of ethyl acetate:i-hexane:Et3N (15 mL). The filtrate
was washed with brine (2ꢂ20 mL) and the combined aque-
ous phases were extracted with ethyl acetate (2ꢂ20 mL).
The washed filtrate and the organic portions were com-
bined, dried through a 1PS phase separator filter and con-
centrated under reduced pressure, followed by purification
on by silica column chromatography (i-hexane:ethyl ace-
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UPDATES
Palladium(II)-Catalyzed Decarboxylative Heck Arylations
[10] H. A. Dieck, R. F. Heck, J. Org. Chem. 1975, 40, 1083–
1090.
[11] Y. Fujiwara, I. Moritani, M. Matsuda, S. Teranishi, Tet-
rahedron Lett. 1968, 3863–3865.
General Procedure for Palladium Complex Synthesis
Exemplified in the Synthesis of 5
Heck product 3a (74 mg, 0.3 mmol) was dissolved in DMF
(1 mL) in
a glass vial and stirred to homogeneity.
[12] X. Du, M. Suguro, K. Hirabayashi, A. Mori, Org. Lett.
Pd(O2CCF3)2 (99.5 mg, 0.3 mmol) and 6-methyl-2,2’-bipyri-
ACHTUNGTRENNUNG
2001, 3, 3313–3316.
dine (61 mg, 0.36 mmol) were dissolved in DMF (1 mL) in
another glass vial and stirred to homogeneity. The two solu-
tions were then mixed to give 2 mL of reaction mixture,
which was stirred at room temperature for 2 h. The reaction
mixture was filtered with a syringe filter to remove small
particles (only visible using a magnifying glass), after which
diethyl ether was added to precipitate 5. The precipitate was
filtered off to give palladium complex 5 as a yellow solid;
yield 50 mg (26%); 1H NMR (400 MHz, CDCl3): d=8.68
(dd, J=5.8, 1.7 Hz, 1H), 8.37–8.32 (m, 1H), 8.19–8.13 (m,
2H), 7.94–7.88 (m, 1H), 7.56–7.52 (m, 1H), 7.41–7.36 (m,
2H), 6.65 (d, J=8.5 Hz, 2H), 5.51 (s, 1H), 3.70 (s, 6H), 3.49
(t, J=7.3 Hz, 2H), 2.72–2.67 (m, 2H), 2.54–2.52 (m, 3H),
2.14–2.05 (m, 2H); 13C NMR (100 MHz, CDCl3): d=170.34,
162.36, 162.07, 161.77, 158.17, 157.72, 153.15, 149.21, 140.44,
139.73, 130.59, 128.82, 126.45, 126.37, 125.51, 124.32, 120.51,
117.32, 111.69, 104.16, 55.40, 50.44, 34.70, 31.46, 29.47, 22.82,
18.36; HR-MS (ESI+): m/z=522.1017, calcd. for
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Acknowledgements
We thank the Swedish Research Council and the Knut and
Alice Wallenberg Foundation for financial support. The au-
thors also acknowledge Dr. Luke Odell, Dr. Christian Skçld,
Dr. Jonas Sꢀvmarker and Fredrik Svensson for helpful dis-
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