Palladium-catalyzed alkoxycarbonylation of terminal alkenes to produce α,β-unsaturated esters: The key role of acetonitrile as a ligand

Article abstract of DOI:10.1002/chem.201304798

A mild protocol has been developed for the Pd^II-catalyzed alkoxycarbonylation of terminal olefins to produce α,β-unsaturated esters with a wide range of substrates. Key features are the use of MeCN as solvent (and/or ligand) to control the reactivity of the intermediate Pd complexes and the combination of CO with O₂, which facilitates the Cu^II-mediated reoxidation of the Pd⁰ complex to Pd ^II and prevents double carbonylation. Acetonitrile is the key! A mild protocol has been developed for the Pd^II-catalyzed alkoxycarbonylation of terminal olefins to produce α,β-unsaturated esters with a wide range of substrates (see scheme). Key features are the use of MeCN as a solvent (and/or ligand) to control the reactivity of the intermediate Pd complexes and the combination of CO with O₂, which facilitates the Cu^II-mediated reoxidation of Pd⁰ to Pd^II and prevents double carbonylation.

Full text of DOI:10.1002/chem.201304798

DOI: 10.1002/chem.201304798
Communication
&
Carbonylation
Palladium-Catalyzed Alkoxycarbonylation of Terminal Alkenes To
Produce a,b-Unsaturated Esters: The Key Role of Acetonitrile as
a Ligand
[a]
[a]
[b]
[c, d]
ˇ
´
Andrei V. Malkov,* Nolwenn Derrien, Maciej Barłꢀg, and Pavel Kocovsky*
Dedicated to Professor Bjçrn ꢀkermark on the occasion of his 80th birthday
Abstract: A mild protocol has been developed for the
PdII-catalyzed alkoxycarbonylation of terminal olefins to
produce a,b-unsaturated esters with a wide range of sub-
strates. Key features are the use of MeCN as solvent (and/
or ligand) to control the reactivity of the intermediate Pd
complexes and the combination of CO with O2, which fa-
cilitates the CuII-mediated reoxidation of the Pd0 complex
Scheme 1. Oxidative alkoxycarbonylation of alkenes.
to PdII and prevents double carbonylation.
practical method currently exists for directing the reaction se-
lectively towards a,b-unsaturated esters 4.
Carbon monoxide is an essential building block, allowing the
transformation of readily available starting materials into more
functionalized products, such as dyes, pharmaceuticals, and
agrochemicals.[1] Oxidative alkoxycarbonylation of terminal al-
kenes 1 with CO in the presence of alcohols, catalyzed by PdII,
is an important synthetic method because it allows the intro-
duction of up to two functional groups into the molecule
(Scheme 1).[2] Depending on the conditions, the reaction can
result in three types of products: b-alkoxy esters 2 (route a),
succinate derivatives 3 (route b), and a,b-unsaturated esters 4
(route c).[3] The first two routes have been extensively investi-
gated, including mechanistic analysis and the development of
enantioselective pathways.[4] By contrast, no adequate and
Previous reports on the synthesis of cinnamic esters by the
carbonylation of styrene employed polymetallic systems, such
as PdCl2/CuCl2/MgCl2/NaOAc[5] or PdCl2/CuCl2/Mn(OAc)2,[6] but
the product yields and catalyst turnovers were low. Bianchini[7]
reported on a selective formation of methyl cinnamate by
using a Pd–diphosphine system. Depending on the conditions,
and the nature of the phosphine ligand, either methyl cinna-
mate (selectivityꢀ99% at 75% conversion) or the respective
dimethyl succinate derivative (selectivityꢀ88%), was pro-
duced; however, the reaction required high CO pressure
(800 psi) and elevated temperatures (808C). Oxidative methoxy-
carbonylation of styrene, catalyzed by PdII complexes with 1,1’-
(diphenylphosphino)-metallocene ligands, was shown to occur
at lower CO pressures (43 psi),[8] although at the expense of
the conversion and chemoselectivity of the reaction. Recently,
a Pd-catalyzed oxidative carbonylation of terminal alkenes, to
afford b,g-unsaturated esters, has been reported[9] and the re-
action is believed to proceed by means of p-allyl Pd complexes
generated by CH insertion.[10] However, the scope of this reac-
tion appears to be limited to allylarenes with reactive CꢁH
bonds in the benzylic position (e.g., PhCH2CH=CH2).
[a] Prof. Dr. A. V. Malkov, N. Derrien
Chemistry Department
Loughborough University
Leicestershire, LE11 3TU (UK)
Fax: (+44)1509 22 3925
E-mail: A.Malkov@lboro.ac.uk
[b] Dr. M. Barłꢁg
Department of Chemistry,
Texas A&M University at Qatar, P.O. Box 23874
Doha (Qatar)
Herein, we present a mild protocol for the oxidative
methoxycarbonylation of terminal alkenes 1!4, under an at-
mospheric pressure of CO, with a wide substrate range and
good functional-group tolerance, resulting in a,b-unsaturated
esters.
In the course of our work on PdII-catalyzed carbonylative
cyclization of olefinic carbamates,[11] we noticed that when the
reaction was carried out in MeCN, an a,b-unsaturated ester of
type 4 was formed; this outcome was found to be specific to
the use of MeCN. We then set out to investigate this transfor-
mation in detail, with the aim to develop a new protocol for
the carbonylation of alkenes and to obtain products that
ˇ
´
[c] Prof. Dr. P. Kocovsky
Department of Organic Chemistry, Arrhenius Laboratory
Stockholm University
Stockholm SE 10691 (Sweden)
E-mail: pavel@organ.su.se
ˇ
´
[d] Prof. Dr. P. Kocovsky
On leave from Department of Chemistry, WestChem
University of Glasgow
Glasgow, G12 8QQ (UK)
E-mail: pavelk@chem.gla.ac.uk
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304798.
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Communication
Table 1. Optimization of chemoselectivity in the oxidative carbonylation
of homoallylic carbonate 5a catalyzed by Pd species.[a]
Table 2. Further optimization of the reaction conditions for the oxidative
carbonylation of 5a.[a]
Entry
Catalyst
[10 mol%] [3 equiv]
Oxidant
Conversion [%][b] Ratio 6a/7a[c]
Entry
Catalyst
[5 mol%]
Additive
Solvent
Yield [%][b]
1
2
3
4
5
6
Pd(OAc)2
Pd(TFA)2
PdCl2
PdCl2
PdCl2
p-BQ
p-BQ
p-BQ
CuCl2
FeCl3·6H2O
Cu(OAc)2·2H2O 12
SM
50
70
SM
SM
–
1
2
3
4
5
6
7
8
PdCl2
–
–
–
–
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN[g]
THF
78[c]
62
14:86
17:83
–
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
[PdCl2(MeCN)2]
[PdCl2(MeCN)2]
[PdCl2(MeCN)2]
20[d]
52
–
–
SM[e]
37[f]
SM
42[f]
SM
82
PdCl2
>99:1
DMSO [10 mol%]
pyridine [10 mol%]
CH(OEt)3 [10 mL]
–
–
–
–
[a] The reactions were carried out on a 0.50 mmol scale. A solution of the
substrate in MeOH (4 mL) was added to a mixture of PdII catalyst
(10 mol%) and oxidant (3 equiv) in MeCN (8 mL), under a CO atmosphere
(balloon). The reaction mixture was then stirred at 608C for 24 h. [b] The
conversion was calculated from the 1H NMR spectra by using naphtha-
lene as an internal standard; SM=starting material. [c] Calculated from
9
10
11
12
MeCN
MeCN
THF
48[d]
72
1
the H NMR spectra of the crude mixtures.
[a] The reactions were carried out on a 0.50 mmol scale. Firstly, a mixture
of the PdII catalyst (5 mol%), Cu(OAc)2·2H2O (1.2 equiv), and Bu4N+Brꢁ
(10 mol%) in a solvent (8 mL) was stirred under a CO atmosphere (bal-
loon), at 408C for 2 h, followed by addition of a solution of the substrate
in MeOH (4 mL) and then by introduction of O2 (second balloon). The re-
action mixture was then stirred at 608C for 48 h. [b] Isolated yield; SM=
starting material. [c] See entry 1 in Table 3. [d] Carried out in the absence
of Bu4N+Brꢁ. [e] Carried out in the absence of Cu(OAc)2·2H2O. [f] Succi-
nate 7a was formed as a major product (6a/7a 1:9). [g] Anhydrous
Cu(OAc)2 was used.
would normally be prepared by Wittig-type chemistry or olefin
metathesis. To this end, the homoallylic carbonate, 5a, with
a terminal C=C bond, was chosen as a functionalized model
substrate. The initial reactions were carried out under 1 atm of
CO in the presence of a PdII catalyst and various oxidants, with
MeCN as a solvent (Table 1).
Initially, p-benzoquinone (p-BQ)[12] was evaluated as an oxi-
dant with various palladium sources. Pd(OAc)2 proved to be in-
efficient (Table 1, entry 1), whereas moderate conversions were
attained with Pd(TFA)2 (TFA=CF3CO2; 50%, entry 2) and PdCl2
(70%, entry 3). However, in both cases succinate 7a, resulting
from a double carbonylation, was identified as the major prod-
uct, whereas the desired unsaturated ester, 6a, was formed in
minor quantities. Metal oxidants, CuCl2 or FeCl3·6H2O, failed to
show any conversion (entries 4 and 5). By contrast, the use of
Cu(OAc)2·2H2O gave exclusively the unsaturated ester 6a, al-
though with only 12% conversion (entry 6). In the latter in-
stance, rapid precipitation of palladium black was observed,
blocking further reaction progress.
the reaction mixture required vigorous stirring to prevent pre-
cipitation of Pd; any deposit appearing on the walls of the
flask was easily redissolved by swirling.
[15]
Replacing PdCl2 with Pd(OAc)2 or Pd(TFA)2
resulted in
slightly reduced yields (62 and 52%, respectively; Table 2, en-
tries 2 and 4). In the absence of a halide ion the reaction
stopped at low conversion (20%), owing to the premature pre-
cipitation of Pd black (entry 3). As expected, no reaction was
observed when molecular oxygen was used as the sole oxidant
(entry 5), demonstrating that both oxygen and CuII are prereq-
uisites for efficient reoxidation. Addition of 10% DMSO to the
reaction mixture (entry 6), known to accelerate reoxidation and
prevent the precipitation of Pd black,[16] resulted in the forma-
tion of a complex mixture, with succinate 7a being the main
component. Pyridine, which is also known to facilitate the re-
oxidation of Pd0 species to PdII,[17] completely inhibited the re-
action (entry 7); however, precipitation of the catalyst was not
observed in this instance, suggesting that pyridine can com-
pete with the substrate for coordination at the metal center.
Acids, such as HCl and p-TsOH (TsOH=toluene sulfonic acid)
were also found to inhibit the reaction, by eliciting a rapid pre-
cipitation of Pd black. Under anhydrous conditions, using
Cu(OAc)2 and triethyl orthoformate,[18] the reaction switched to
double carbonylation (entry 8). In THF, no conversion was ob-
served (entry 9).
To improve the conversion, we had to ensure a facile reoxi-
dation of the Pd0 species to PdII, preventing agglomeration of
the reduced Pd species and the subsequent precipitation of Pd
black. After some experimentation, and following successful
examples of Wacker-type oxidation chemistry,[13] we found that
the use of an extra balloon of oxygen dramatically enhanced
the regeneration of our palladium system. Thus, employing
a 1:1 CO/O2 atmosphere, the a,b-unsaturated ester, 6a, was
obtained in 78% yield (Table 2, entry 1). Notably, this protocol
also allowed a decrease in the PdCl2 loading to 5 mol% and
Cu(OAc)2·2H2O to 1.2 equivalents. Tetrabutylammonium bro-
mide, used to prevent the formation of colloidal Pd0species,[14]
proved to be another important component of the reaction
mixture and poor yields were obtained in its absence. On the
other hand, the use of iodide Bu4N+Iꢁ resulted in the forma-
tion of succinate 7a as a major product. We also found that
These experiments allowed us to formulate a protocol with
the following reaction conditions: the PdII and CuII salts should
be dissolved in MeCN and the mixture should be heated at
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Communication
408C for 2 h under an atmosphere of CO, prior to the addition
of a solution of the substrate in methanol.[19] This optimized
protocol appears to indicate that MeCN plays an important
role in the formation of the catalytically active species. The
next experiments were, therefore, carried out with
[(MeCN)2PdCl2] as a catalyst. In MeCN, 6a was obtained in high
yield (82%, entry 10), and the reaction was found to proceed
even in THF, previously identified as an unsuitable solvent
(72%, entry 12; compare with entry 9). In the absence of
Bu4N+Brꢁ, the reaction afforded 6a in lower yield (48%,
entry 11), reflecting the premature precipitation of Pd black
(see also entry 3).
tert-butanol, the respective tert-butyl ester, 6c’, was isolated in
63% yield (entry 4). The presence of an alkyl substituent in the
a-position of the C=C bond[20] did not affect the reactivity (6h,
62%; entry 9).
Related homoallylic amine derivatives 5i–n were then inves-
tigated (Table 3, entries 10–15). Primary phthalimide 5i reacted
uneventfully (72%), but secondary phthalimides 5j and 5l ex-
hibited poor conversion, resulting in low isolated yields (40%
and 12%, respectively). Carbonylation of carbamates 5k and
5m and tosylamide 5n proceeded in acceptable yields (en-
tries 12, 14, and 15). A general feature in all of these carbonyla-
tions was the formation of minor quantities of b,g-isomers 8,
along with the expected a,b-unsaturated esters 6 in all but
one case (6k). It is noteworthy that the latter shift of the
double bond (entries 10, 11, and 13–15) was not commonly
observed in the carbonate series (entries 2–9), except for 5a
(entry 1), and, thus, seems to be characteristic of amides and
imides, possibly originating from the enhanced propensity of
these groups to coordinate Pd[11a] and other species,[21] affect-
ing the reactivity of the intermediate complex.
After establishing the optimal conditions, the reaction scope
was investigated by employing various terminal alkenes. The
first group consisted of an extended range of homoallylic car-
bonates 5a–h (Table 3, entries 1–9). The tert-butoxycarbonyl
Table 3. Oxidative alkoxycarbonylation of homoallylic carbonates and
amides catalyzed by Pd.[a]
The reaction scope was further elucidated by using terminal
alkenes 9a–j (Table 4). Thus, the methoxycarbonylation of sty-
rene afforded methyl cinnamate 10a (87%), but when the re-
Table 4. Oxidative methoxycarbonylation of alkenes.[a]
Entry
1
5
R1, R2, X
6 or 8
R3
Yield [%][b]
5a
H, H, OCO2Me
6a/8a
(7:1)
6b
6c
6c’
Me 78
2
3
4
5
6
7
8
9
5b
5c
5c
5d
5e
5 f
5g
5h
5i
H, H, OCO2tBu
Ph, H, OCO2Me
Ph, H, OCO2Me
4-NO2C6H4, H, OCO2Me
Me 52
Me 86
tBu 63
Me 72
Me 66
Me 63
Me 65
Me 62
Me 72
6d
3,4-(MeO)2C6H3, H, OCO2Me 6e
2-thienyl, H, OCO2Me
nC5H11, H, OCO2Me
Ph, Me, OCO2Me[c]
H, H, phthalimide
6 f
6g
6h
6i/8i
(2.5:1)
6j/8j
(6:1)
6k
10
11
5j
Ph, H, phthalimide
Me 40[d]
12
13
5k
5l
Ph, H, NHCbz
nC5H11, H, phthalimide
Me 60
Me 12[d]
6l/8l
(3:1)
14
15
5m nC5H11, H, NHCbz
5n nC5H11, H, NHTs
6m/8m Me 58
(2.5:1)
6n/8n
Me 53
(3:1)
[a] The reactions were carried out on a 0.25–0.67 mmol scale. A mixture
of PdCl2 (5 mol%), Cu(OAc)2·2H2O (1.2 equiv), MeCN (8 mL) was stirred
under a CO atmosphere (balloon), at 408C for 2 h, prior to the addition of
a solution of the substrate (ꢂ0.1 g) in R3OH (4 mL) and the introduction
of an O2 balloon. The reaction mixture was then stirred at 608C for 24 h.
Cbz=carbobenzyloxy, Ts=tosyl. [b] Isolated yield. [c] The syn-isomer of
5h was employed. [d] Poor conversion.
[a] For conditions see Table 3.
(Boc) group turned out to be less suitable than methoxycar-
bonyl, as reflected in the reduced yield of 6b (52%, entry 2;
compare with entry 1). Secondary carbonates with aryl (6c–e),
heteroaryl (6 f), and alkyl substituents (6g) were obtained in
good yields (63–86%, entries 3–8). By replacing methanol with
action was carried out in tert-butanol instead of methanol, the
yield (of 10a’) dropped to 63%, presumably owing to the in-
creased steric bulk. Electron-rich and electron-poor styrenes
(9b and 9c) readily produced the respective cinnamic esters
10b and 10c in good yields (70 and 62%, respectively). Car-
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bonylation of p-divinylbenzene 9d afforded diester 10d (82%),
with only traces of the monocarbonylated product detected.
The cyclohexyl analogue, 10e, isoxazolidine 10 f, and bromo
derivative 10g were obtained in practical yields (58–62%).
Carbonylation of the allyl silyl ether 9h was accompanied by
removal of the TMS group and a change in the position of the
double bond, resulting in the formation of g-keto ester 10h
(65%).[22]
The latter assumption is in line with the hypothesis that CO
would not displace the remaining MeCN (as in A) under atmos-
pheric pressure. However, the actual mechanism could be
more complex, as Cu(OAc)2 is likely to play an additional role,
by interacting with the Pd complex.[25]
An alternative mechanism, involving chloropalladation[26] fol-
lowed by HCl elimination, can be ruled out, since the reaction
was found to proceed in the absence of halide ions (Table 2,
entries 3 and 11), though less efficiently because of the prema-
ture precipitation of Pd black.[27]
Two products were obtained from allyl benzene 9i, namely
the expected a,b-unsaturated ester, 10i, and its b,g-isomer, 11,
in a 1:3 ratio. Conjugation with the aromatic ring thus appears
to be preferred over conjugation with the ester group. In a sim-
ilar way, a-methylstyrene (9j) furnished 10j, presumably arising
from the corresponding p-allyl Pd-complex. However, the reac-
tion was sluggish, apparently owing to the steric hindrance;
the product was formed in mere 20% yield.
In order to illustrate the practical use of this new method,
we resolved to synthesize the vanilloid receptor-1 antagonist
TRPV-1 (16)[28] on a gram scale (Scheme 3). Under our standard
According to the widely accepted mechanism,[4] PdCl2 and
CO react with an olefin (in the absence of MeCN) to generate
the corresponding h2-complex, which can react with MeOH
either at the CꢃO or C=C ligand, eventually giving rise to 2 or
3, depending on the actual conditions.[4]
To account for the key role of MeCN, which promotes the
formation of a,b-unsaturated esters 4 at the expense of 2 and
3 (Scheme 2), it can be reasoned that MeCN, as a ligand com-
Scheme 3. Synthesis of the potent vanilloid receptor antagonist 16.
conditions, methoxycarbonylation of 4-tert-butylstyrene (12) af-
forded ester 13 (85%), which was then hydrolyzed to furnish
acid 14. The synthesis was completed by the conversion of 14
into the corresponding acid chloride, the reaction of which (in
situ), with the aniline derivative 15, afforded the target amide
16 in 62% yield over two steps (not optimized). The synthesis
of 16 (920 mg) was, therefore, accomplished in three simple
operations in 44% overall yield.
Scheme 2. Proposed mechanism for carbonylation (L=MeCN).
peting with CO, affects the reactivity of the Pd complex.[23]
Thus, [(MeCN)2PdCl2], either used as such or generated in situ,
when mixed with CO, can undergo a ligand exchange. It can
be conjectured, however, that only one molecule of MeCN is
replaced with CO in the equilibrium to generate the reactive
complex A (L=MeCN), otherwise, if both molecules of MeCN
were replaced, the reaction would follow the scenario dis-
cussed in the previous paragraph, giving rise to 2 or 3. Nota-
bly, the optimized reaction conditions require that the catalyst
and CO (in MeCN) are allowed to “mature” before the olefin is
added, indicating that an equilibrium needs to be reached
prior to the reaction with the olefin. Complex A can then react
with MeOH (added as a solvent of the substrate) to produce
B,[24] which would then coordinate the olefin upon replace-
ment of one of the MeCN molecules. The resulting complex, C,
would then undergo olefin insertion to generate D. The latter
complex, with MeCN in the coordination sphere of the Pd
center, can then be assumed to react differently, compared
with its counterpart lacking the MeCN ligand, and prefer b-H
elimination over the second carbonylation, thus producing 4.
In conclusion, a mild protocol has been developed for the
Pd-catalyzed alkoxycarbonylation of terminal alkenes to pro-
duce a,b-unsaturated esters (1!4) with a wide range of sub-
strates. The reaction conditions, including PdCl2 (5 mol%),
Cu(OAc)2 (1.2 equivalents), CO/O2 (1 atm), MeOH, and MeCN as
a solvent, were optimized to attain good yields (60–87% in
most cases) and high chemoselectivity. Significantly, the reac-
tion proceeds under an atmospheric pressure of CO and O2
(from two individual balloons), preventing the double carbony-
lation pathway and Pd-black precipitation. The use of oxygen
as the second gas, which facilitates the reoxidation of the Pd0
species to PdII, mediated by CuII, and the key role of MeCN as
a solvent (and Pd ligand) is particularly noteworthy. This new
protocol can serve as an attractive alternative to the existing
methods for the synthesis of a,b-unsaturated esters, such as
Wittig-type alkenylation, cross-metathesis, Heck addition, and
Suzuki–Miyaura coupling.[29] Of these methods, the new proto-
col is the most atom economical and sustainable because only
two protons are lost from the reactants (one from the sub-
strate olefin and one from MeOH).
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[10] a) D. Milstein, Organometallics 1982, 1, 888–890; b) B. C. Sçderberg, B.
ꢃkermark, S. S. Hall, J. Org. Chem. 1988, 53, 2925–2937.
Experimental Section
[11] a) A. V. Malkov, M. Barłꢀg, L. Miller-Potuckꢄ, M. A. Kabeshov, L. J. Farru-
General Procedure
ˇ
´
gia, P. Kocovsky, Chem. Eur. J. 2012, 18, 6873–6884. For our earlier
A 50 mL round-bottomed flask was charged with PdCl2 (5 mol%)
and Cu(OAc)2·2H2O (1.1 equivalents) and flushed first with N2, fol-
lowed by CO. A CO balloon (diameter ꢂ15 cm) was then applied,
MeCN (8 mL) was introduced by a syringe, and the reaction mix-
ture was left to stir at 408C for 2 h. A solution of the substrate
(0.5 mmol) in MeOH (4 mL) was added by a syringe, and an O2 bal-
loon (diameter ꢂ7 cm) was applied. The reaction mixture was
stirred at 608C for 24 h and then cooled. Ether (15 mL) was added
and the mixture was washed with aqueous saturated NaHCO3 and
brine and then dried over MgSO4. The solvent was evaporated
under vacuum and the residue was purified by flash chromatogra-
phy on silica gel (petroleum ether/Et2O 90:10) to afford a pure
product. Note: a palladium deposit may occur during the reaction,
but this can be easily re-dissolved by gentle shaking or swirling.[30]
ˇ
´
work, see: b) P. Kocovsky, M. Pour, J. Org. Chem. 1990, 55, 5580–5589.
[12] For reviews on the use of p-BQ, CuII, and other oxidants of Pd inter-
mediates, see: a) J.-E. Bꢅckvall, Acc. Chem. Res. 1983, 16, 335–342;
b) P. G. Andersson, J.-E. Bꢅckvall, in Handbook of Organopalladium
Chemistry for Organic Synthesis (Eds.: E. Negishi, A. de Meijere), Wiley,
New York, 2002, Vol. 2, pp. 1859–1874; For interception of the p-BQ-Pd
complex as intermediate, see: c) H. Grennberg, A. Gogoll, J.-E. Bꢅckvall,
Organometallics 1993, 12, 1790–1793. For another use of p-BQ in the
transmetalation of organomercurials with PdII, followed by carbonyla-
ˇ
´
tion, see: d) P. Kocovsky, J. M. Grech, W. L. Mitchell, Tetrahedron Lett.
ˇ
ˇ
´
1996, 37, 1125–1128; e) P. Kocovsky, V. Dunn, J. M. Grech, J. Srogl, W. L.
Mitchell, Tetrahedron Lett. 1996, 37, 5585–5588.
[13] a) J. Tsuji, I. Shimizu, K. Yamamoto, Tetrahedron Lett. 1976, 17, 2975–
2976; b) T. Hosokawa, T. Uno, S. Inui, S. I. Murahashi, J. Am. Chem. Soc.
1981, 103, 2318–2323; c) T. Nishimura, N. Kakiuchi, T. Onoue, K. Ohe, S.
Uemura, J. Chem. Soc. Perkin Trans. 1 2000, 1915–1918; d) B. Weiner, A.
Baeza, T. Jerphagnon, B. L. Feringa, J. Am. Chem. Soc. 2009, 131, 9473–
9474.
[14] a) M. H. G. Prechtl, J. D. Scholten, J. Dupont, Molecules 2010, 15, 3441–
3461; b) D. Zim, A. L. Monteiro, J. Dupont, Tetrahedron Lett. 2000, 41,
8199–8202; c) V. Calꢆ, P. Giannocaro, A. Nacci, A. Monopoli, J. Mol.
Catal. A 2004, 214, 45–56. For other effects of halide ions (in particular
Clꢁ) on the Pd-catalyzed reactions, see, e.g., ref. [12a,b] and the follow-
Experimental procedures, analytical and spectral data, and copies
of the NMR spectra for the key compounds are available in the
Supporting Information.
Acknowledgements
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ing: d) P. Kocovsky, S. Vyskocil, I. Cꢇsarovꢄ, J. Sejbal, I. Tislerovꢄ, M. Smrci-
We thank the EPSRC for grant EP/E011179/1 and Loughbor-
ough University for a fellowship to N. D. and other support.
The Axel Wenner–Gren sabbatical scholarship awarded to P. K.
and the additional support from COST through the ORCA
action are also appreciated.
na, G. C. Lloyd-Jones, S. C. Stephen, C. P. Butts, M. Murray, V. Langer, J.
Am. Chem. Soc. 1999, 121, 7714–7715; e) P. Kocovsky, A. V. Malkov, S Vy-
skocil, G. C. Lloyd-Jones, Pure Appl. Chem. 1999, 71, 1425–1433; f) G. C.
Lloyd-Jones, S. C. Stephen, M. Murray, C P. Butts, S. Vyskocil, P. Kocovsky,
Chem. Eur. J. 2000, 6, 4348–4357; g) I. J. S. Fairlamb, G. C. Lloyd-Jones,
S. Vyskocil, P. Kocovsky, Chem. Eur. J. 2002, 8, 4443–4453; h) L. Gouriou,
ˇ
ˇ
´
ˇ
ˇ
ˇ
ˇ
´
ˇ
ˇ
ˇ
´
ˇ
ˇ
ˇ
´
G. C. Lloyd-Jones, S. Vyskocil, P. Kocovsky, J. Organomet. Chem. 2003,
687, 525–537.
Keywords: carbonylation · homogeneous catalysis · oxygen ·
palladium · solvent effects
[15] For an early use of Pd(TFA)2 in PdII-catalyzed reactions, see: a) J. E.
ˇ
´
McMurry, P. Kocovsky, Tetrahedron Lett. 1984, 25, 4187–4190; b) J. E.
ˇ
´
McMurry, P. Kocovsky, Tetrahedron Lett. 1985, 26, 2171–2172.
[16] a) B. A. Steinhoff, S. R. Fix, S. S. Stahl, J. Am. Chem. Soc. 2002, 124, 766–
767; b) T. Diao, P. White, I. Guzei, S. S. Stahl, Inorg. Chem. 2012, 51,
11898–11909.
[1] B. Cornils, W. A. Herrmann, Applied Homogeneous Catalysis with Organo-
metallic Compounds; Vol. 5: Applications, 2nd ed., Wiley-VCH, Weinheim,
2002, pp. 31–194.
[17] B. V. Popp, S. S. Stahl, Chem. Eur. J. 2009, 15, 2915–2922.
[18] For the use of MeC(OR)3 or HC(OR)3 in PdII-catalyzed reactions, see
ref. [11a] and the following: a) H. Harayama, A. Abe, T. Sakado, M.
Kimura, K. Fugami, S. Tanaka, Y. Tamaru, J. Org. Chem. 1997, 62, 2113–
2122; b) B. Gabriele, L. Veltri, V. Maltese, R. Spina, R. Mancuso, G. Sale-
rno, Eur. J. Org. Chem. 2011, 5626–5635; c) B. Gabriele, R. Mancuso, G.
Salerno, L. Veltri, M. Costa, A. Dibenedeto, ChemSusChem 2011, 4,
1778–1786.
[2] a) P. P. Chiusoli, M. Costa in Handbook on Organopalladium Chemistry for
Organic Synthesis Vol. 2, (Eds.: E. Negishi, A. de Meijere), Wiley, New
York, 2002, pp. 2593–2623; b) J. Tsuji, Palladium Reagents and catalysts,
Wiley-VCH, Weinheim, 2004, pp. 45–50; c) B. Gabriele, G. Salerno, M.
Costa, Top. Organomet. Chem. 2006, 18, 239–272.
[3] X.-F. Wu, H. Neumann, M. Beller, ChemSusChem 2013, 6, 229.
[4] a) R. F. Heck, J. Am. Chem. Soc. 1969, 91, 6707–6714; b) R. F. Heck, J.
Am. Chem. Soc. 1971, 93, 6896–6901; c) R. F. Heck, J. Am. Chem. Soc.
1972, 94, 2712–2716; d) D. M. Fenton, P. J. Steinwand, J. Org. Chem.
1972, 37, 2034–2035; e) D. E. James, L. F. Hines, J. K. Stille, J. Am. Chem.
Soc. 1976, 98, 1806; f) D. E. James, J. K. Stille, J. Am. Chem. Soc. 1976,
98, 1810–1823; g) D. Zargarian, H. Alper, Organometallics 1991, 10,
2914–2921; h) S. C. A. Nefkens, M. Sperrle, G. Consiglio, Angew. Chem.
1993, 105, 1837–1838; Angew. Chem. Int. Ed. 1993, 32, 1719–1720; i) H.
Zhou, J. Hou, J. Cheng, S. Lu, H. Fu, H. Wang, J. Organomet. Chem.
1997, 543, 227–228.
[19] The protocol was modified from ref. [11a].
[20] For the stereocontrolled synthesis of the parent alcohols, see: a) A. V.
Malkov, M. Orsini, D. Pernazza, K. W. Muir, V. Langer, P. Meghani, P. Ko-
ˇ
´
covsky, Org. Lett. 2002, 4, 1047–1049; b) A. V. Malkov, M. Bell, M. Orsini,
ˇ
´
D. Pernazza, A. Massa, P. Herrmann, P. Meghani, P. Kocovsky, J. Org.
Chem. 2003, 68, 9659–9668; c) A. V. Malkov, M. Bell, M. Vassieu, V. Bu-
ˇ
´
gatti, P. Kocovsky, J. Mol. Catal. A 2003, 196, 179–186; d) A. V. Malkov, L.
ˇ
´
Dufkovꢄ, L. Farrugia, P. Kocovsky, Angew. Chem. 2003, 115, 3802–3805;
Angew. Chem. Int. Ed. 2003, 42, 3674–3677; e) A. V. Malkov, M. Bell, F.
[5] G. Cometti, G. P. Chiusoli, J. Organomet. Chem. 1979, 181, C14–C16.
[6] A. R. El’man, O. V. Boldyreva, E. V. Slivinskii, S. M. Loktev, Russ. Chem.
Bull. 1992, 41, 435–438.
ˇ
´
Castelluzzo, P. Kocovsky, Org. Lett. 2005, 7, 3219–3222; f) A. V. Malkov,
ˇ
M.-M. Westwater, A. Gutnov, P. Ramꢇrez-Lꢀpez. F. Friscourt, A. Kadlcꢇ-
ˇ
ˇ
´
[7] C. Bianchini, G. Mantovani, A. Meli, W. Oberhauser, P. Brꢂggeller, T.
Stampfl, J. Chem. Soc. Dalton Trans. 2001, 690–698.
kovꢄ, J. Hodacovꢄ, Z. Rankovic, M. Kotora, P. Kocovsky, Tetrahedron
2008, 64, 11335–11348; g) A. V. Malkov, M. Bell, P. Ramꢇrez-Lꢀpez, L. Bie-
ˇ ˇ
´
dermannovꢄ, L. Rulꢇsek, L. Dufkovꢄ, M. Kotora, F. Zhu, P. Kocovsky, J.
[8] C. Bianchini, A. Meli, W. Oberhauser, S. Parisel, O. V. Gusev, A. M. Kal’sin,
N. V. Vologdin, F. M. Dolgushin, J. Mol. Catal. A 2004, 224, 35.
[9] a) H. Chen, C. Cai, X. Liu, X. Li, H. Jiang, Chem. Commun. 2011, 47,
12224–12226. For the synthesis of b,g-unsaturated esters by carbonyla-
tion of allylic alcohols, see: b) B. Gabriele, G. Salerno, M. Costa, G. P.
Chiusoli, J. Mol. Catal. A 1996, 111, 43–48; c) Q. Liu, L. Wu, H. Jiao, X.
Fang, R. Jackstell, M. Beller, Angew. Chem. 2013, 125, 8222–8226;
Angew. Chem. Int. Ed. 2013, 52, 8064–8068.
ˇ
´
Am. Chem. Soc. 2008, 130, 5341–5348; h) P. Kocovsky, A. V. Malkov, Pure
ˇ
Appl. Chem. 2008, 80, 953–966; i) A. V. Malkov, S. Stoncius, M. Bell, F.
ˇ
Castelluzzo, P. Ramꢇrez-Lꢀpez, L. Biedermannovꢄ, L. Rulꢇsek, V. Langer, P.
ˇ
´
Kocovsky, Chem. Eur. J. 2013, 19, 9167–9185.
ˇ
´
ˇ
´
[21] a) P. Kocovsky, Tetrahedron Lett. 1988, 29, 2475–2478; b) P. Kocovsky, I.
´
Stary, J. Org. Chem. 1990, 55, 3236–3243. For an overview of the related
coordination of Rh species to amide groups in catalytic hydrogenation
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Chem. Eur. J. 2014, 20, 4542 – 4547
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Communication
affording amino acids, see: C. Nꢄjera, J. M. Sansano, Chem. Rev. 2007,
107, 4584–4671.
[28] E. M. Doherty, C. Fotsch, Y. Bo, P. P. Chakrabarti, N. Chen, N. Gavva, N.
Han, M. G. Kelly, J. Kincaid, L. Klionsky, Q. Liu, V. I. Ognyanov, R. Tamir, X.
Wang, J. Zhu, M. H. Norman, J. J. S. Treanor, J. Med. Chem. 2005, 48, 71–
90.
[22] Allyl silanes R3SiCH2CH=CH2 (R=Me or Ph), subjected to methoxycarbo-
nylation, afforded complex mixtures of products with a loss of the sili-
con group. This behavior shows that Pd can readily insert into the OꢁSi
or CꢁSi bond, complicating the reaction.
[29] For comparison of the efficiency of these methods in the synthesis of
ˇ
´
ˇ
´
allylic alcohols, see: J. Stambasky, A. V. Malkov, P. Kocovsky, Collect.
[23] For dramatic ligand effects on the reactivity of Pd complexes, see:
ref. [12d], ref. [12e] and the following: a) R. M. Trend, Y. K. Ramtohul,
B. M. Stoltz, J. Am. Chem. Soc. 2005, 127, 17778–17788; b) T. Hayashi, K.
Yamasaki, M. Mimura, Y. Uozumi, J. Am. Chem. Soc. 2004, 126, 3036–
3037; c) J. S. Nakhla, J. W. Kampf, J. P. Wolfe, J. Am. Chem. Soc. 2006,
128, 2893–2901.
Czech. Chem. Commun. 2008, 73, 705–732.
[30] Although the use of a CO balloon at atmospheric pressure represents
an intrinsic risk, this is a procedure that has been repeatedly used in
the literature as a standard technique. We have not experienced any
problem using balloons of CO and O2. Nevertheless, considering that
they can create highly flammable mixtures, the reactions were carried
out in a well-ventilated fumehood, free from any source of ignition.
Note that the two gasses are mixed in the reaction vessel, whereas the
back-leaking and mixing in the balloons is minimal due to the small
gauge of the needle that connects the balloon with the reaction vessel
through a septum. Furthermore, although the reaction temperature is
kept at 60oC, the balloons experience room temperature, which further
reduces the risk of explosion. To alleviate the hazards of toxicity and
flammability of CO, the reaction can be performed in an autoclave
under the same conditions. In fact, the model reaction (Table 2, entry 1)
was also carried out in a stainless steel autoclave with ꢂ0.5 atm of
each of CO and O2 to give a full conversion of 5a into 6a, with 70%
isolated yield.
[24] Complexes of the type Ln(X)PdCO2Me have been prepared independ-
ently and characterized, see: ref. [4a] and the following: a) F. Rivetti, U.
Romano, J. Organomet. Chem. 1978, 154, 323–326; b) D. Milstein, Acc.
Chem. Res. 1988, 21, 428–434.
[25] For discussion of the interaction of PdX2 species with MYn salts, see,
e.g.: ref. [11b] and the following: a) K. Takehira, T. Hayakawa, H. Orita, M.
Shimidzu, J. Mol. Catal. 1989, 53, 15–21; b) T. Hosokawa, S. Murahashi,
Acc. Chem. Res. 1990, 23, 49–54; c) M. F. Semmelhack, C. Kim, N. Zhang,
C. Budurow, M. Sanner, W. Dobler, M. Meier, Pure Appl. Chem. 1990, 62,
ˇ
´
2035–2040; d) P. Kocovsky, Organometallics 1993, 12, 1969–1971.
[26] J. Tsuji, M. Morikawa, J. Kiji, J. Am. Chem. Soc. 1964, 86, 4851–4853.
[27] A CꢁH activation of the vinylic group could also be suggested, but this
scenario seems less likely in view of the behavior of 9j and in light of
the current work in progress. For recent examples of the true C=CH ac-
tivation, see: N. Gigant, J.-E. Bꢅckvall, Chem. Eur. J. 2013, 19, 10799–
10803 and references therein.
Received: December 6, 2013
Published online on March 11, 2014
Chem. Eur. J. 2014, 20, 4542 – 4547
www.chemeurj.org
4547
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