Regioselective Pd-Catalyzed Methoxycarbonylation of Alkenes Using both Paraformaldehyde and Methanol as CO Surrogates

Article abstract of DOI:10.1002/anie.201410764

In recent years, considerable effort has focused on the development of novel carbonylative transformations using CO surrogates. Consequently, toxic CO gas can be replaced by more convenient inorganic or organic carbonyl compounds. Herein, the first regioselective methoxycarbonylation of alkenes with paraformaldehyde and methanol as CO substitutes is reported. This new procedure is applicable to a series of alkenes in the presence of a palladium catalyst under relatively mild conditions and is highly atom efficient.

Full text of DOI:10.1002/anie.201410764

Angewandte
Chemie
DOI: 10.1002/anie.201410764
Carbonylation
Regioselective Pd-Catalyzed Methoxycarbonylation of Alkenes Using
both Paraformaldehyde and Methanol as CO Surrogates**
Qiang Liu, Kedong Yuan, Percia-Beatrice Arockiam, Robert Franke, Henri Doucet,
Ralf Jackstell, and Matthias Beller*
Abstract: In recent years, considerable effort has focused on
the development of novel carbonylative transformations using
CO surrogates. Consequently, toxic CO gas can be replaced by
more convenient inorganic or organic carbonyl compounds.
Herein, the first regioselective methoxycarbonylation of
alkenes with paraformaldehyde and methanol as CO substi-
tutes is reported. This new procedure is applicable to a series of
alkenes in the presence of a palladium catalyst under relatively
mild conditions and is highly atom efficient.
Scheme 1. Typical CO surrogates (the percentage by molecular weight
of the CO unit is shown in parenthesis).
T
ransition-metal-catalyzed carbonylation reactions have
become a powerful tool in both organic synthesis and
industrial production for constructing various carbonyl com-
pounds such as esters, amides, ketones, and aldehydes.[1]
However, synthetic chemists are still hesitant to apply
carbon monoxide in a more general manner because of its
toxicity and gaseous nature. To solve these problems, the
development of “CO-free” carbonylation methods based on
easy to handle inorganic or organic carbonyl compounds has
attracted substantial interest in the past three decades.[2] The
typical known CO surrogate compounds are listed in
Scheme 1. Unfortunately, most of these alternative carbonyl
resources suffer from significant drawbacks in terms of atom
efficiency, reactivity, toxicity, and price. For example, metal
carbonyls such as [Mo(CO)6] (A) are applied to deliver CO in
various carbonylation reactions.[3] The main disadvantages of
this approach are the presence of stoichiometric amounts of
additional transition metals in the reaction mixture and harsh
reaction conditions for CO release from these toxic metal
carbonyls. Notably, Skrydstrup and co-workers developed
a new technique for the ex situ generation of carbon
monoxide and its application in palladium-catalyzed carbon-
ylation reactions by using a sealed two-chamber system.[4]
Here, near-stoichiometric quantities of CO precursors, includ-
ing “CO gen” (B),[4a] pivaloyl chloride (C),[4a] as well as
silacarboxylic acids (D),[4b] are sufficient to promote carbon-
ylative transformations. N-Formylsaccharin (E) is also known
as a CO source for the palladium-catalyzed reductive carbon-
ylation of aryl halides to access aryl aldehydes.[5] However,
concerns about the atom efficiency and waste generation for
CO alternatives B–E still remain. Hence, cheaper and more
readily available carbonyl reagents are highly desired.
It is well known that CO can be released from formic acid
(F; R = H) by dehydration in sulfuric acid (Morgan reac-
tion).[6] Additionally, olefin carbonylation reactions in the
presence of formic acid as a carbonyl source are also achieved
through sequential dehydrogenation and reverse water gas
shift processes at elevated temperature (> 1508C).[7] More-
over, formates (F; R = alkyl, aryl)[8] and formamides (G)[9]
have also been used for the carbonylation of olefins and aryl
halides. In general, harsh conditions, poor selectivity in the
presence of additional nucleophiles, and/or the necessity for
external CO pressure restrict the further application of formic
acid derivatives as a CO source. CO2 (H) is an ideal C1
building block in organic synthesis due to its abundance,
nontoxicity, and recyclability. Remarkably, the catalytic
in situ generation of CO from CO2 reduction and its
incorporation in the following carbonylation reactions has
been realized.[10] This is a promising process that uses CO2
instead of CO as a C1 resource for carbonylations, but the
substrate scope is so far limited by the required reductants
and the regioselectivity cannot so far be controlled.
[*] Dr. Q. Liu, K. Yuan, Dr. P. Arockiam, Dr. R. Jackstell,
Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse an der Universitꢁt Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
E-mail: matthias.beller@catalysis.de
K. Yuan, Dr. H. Doucet
Institut des Sciences Chimiques de Rennes
UMR6226 CNRS-Universite de Rennes
Campus de Beaulieu, 35042 Rennes Cedex (France)
R. Franke
Evonik Industries AG
Paul-Baumann-Strasse 1, 45772 Marl (Germany)
and
Lehrstuhl fꢀr Theoretische Chemie, 44780 Bochum (Germany)
[**] We thank the State of Mecklenburg-Vorpommern and the BMBF for
financial support. We also thank the analytical team for analytical
support and the insightful discussion with Prof. Serafino Gladiali
and Prof. Carmen Claver. Q.L appreciates a grant from the Alexander
von Humboldt Foundation.
Supporting information for this article (Experimental details) is
available on the WWW under http://dx.doi.org/10.1002/anie.
201410764.
Although methanol is an abundant and potentially renew-
able chemical and can be a potential carbonyl source, this area
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Table 1: Optimization studies for the Pd-catalyzed methoxycarbonylation
of 1-octene (1a).[a]
is underdeveloped because of the high energetic demand for
methanol dehydrogenation.[11] Undoubtedly, the simplest
aldehyde, formaldehyde (J), is the most atom economic CO
surrogate for carbonylation reactions with suitable reactivity.
The percentage by molecular weight of the CO unit in this
molecule is 93%. While the transition-metal-catalyzed decar-
bonylation of higher aldehydes[12] and hydroacylation of
alkenes with aldehydes[13] has been well-established, formal-
dehyde is less applied as a carbonyl source.[14] In fact, to the
best of our knowledge, only two alkoxycarbonylation reac-
tions have been reported by us which uses formaldehyde as
the carbonyl source.[15] More specifically, we developed the
catalytic alkoxycarbonylation of aryl bromides[15a] and also
very recently the first ruthenium-catalyzed alkoxycarbonyl-
ation of alkenes using formaldehyde.[15b] The olefin alkoxy-
carbonylation reaction represents an important approach for
the production of value-added bulk and fine chemicals. For
example, methyl propionate, a key intermediate for polyme-
thacrylates, is produced on a scale of > 300000 tons per year
by the methoxycarbonylation of ethylene.[16] However, in our
previous study, the Ru catalyst does not promote the
regioselective carbonylations of industrially interesting ali-
phatic alkenes. To solve this challenging problem, herein we
report for the first time highly linear selective methoxycar-
bonylation reactions of alkenes by using paraformaldehyde
and methanol as inexpensive and atom-efficient CO surro-
gates simultaneously. This approach offers a convenient syn-
thesis of various methyl esters through a “CO-free” Pd-
catalyzed carbonylative process.
Initially, we examined the feasibility of the Pd-catalyzed
methoxycarbonylation of 1-octene (1a) with paraformalde-
hyde and methanol (2a) to give methyl nonanoate (3a). First,
the activities of different in situ generated palladium phos-
phine complexes were studied. A series of bidentate and
monodentate ligands were tested using palladium(II) acetyl-
acetonate as the catalyst precursor and PTSA as the acid co-
catalyst (see Scheme S1 in the Supporting Information).
Interestingly, almost all of the ligands we examined gave
quite low catalytic activity with less than 5% yield of the
desired product 3a, except for dtbpx [a,a’-bis(di-tert-butyl-
phosphino)-o-xylene], from which a 74% yield of 3a along
with 95% n-selectivity was obtained. It should be noted that
isomerized octenes 4a were generated as by-products in all
the cases. Next, we investigated the impact of key reaction
parameters for the desired transformation (Table 1). After
exploring a wide array of conditions, we found that using
Pd(OAc)2 (1 mol%), dtbpx (4 mol%), PTSA (4 mol%), and
paraformaldehyde (6.7 equiv of -CH2O) in MeOH at 1008C
furnished a good yield (78%) of the desired product with
95% n-selectivity (Table 1, entry 7). Adding an acidic co-
catalyst with a weakly coordinating anion such as PTSA and
MSA, is crucial to the success of this methoxycarbonylation
process (Table 1, entries 1 and 2). Other tested acids did not
afford any carbonylation product 3a (Table 1, entries 3–6).
The effect of different palladium catalyst precursors was also
explored. Pd(OAc)2 and [Pd(acac)2] (acac = acetylacetonate)
showed similarly good reactivity compared to other tested Pd0
and PdII complexes (Table 1, entries 7–13).
Entry [Pd]
Acid
Yield 3a [%] (l/b) Yield 4a [%]
1
2
3
4
5
6
7
8
[Pd(acac)2]
PTSA
MSA
H2SO4
TFA
AcOH
HCO2H 0 (N.D)
PTSA
PTSA
PTSA
74 (95:5)
74 (95:5)
0 (N.D)
0 (N.D)
0 (N.D)
25
24
57
77
89
79
22
99
90
90
99
82
99
[Pd(acac)2]
[Pd(acac)2]
[Pd(acac)2]
[Pd(acac)2]
[Pd(acac)2]
Pd(OAc)2
PdCl2
[Pd(cod)Cl2]
[Pd(MeCN)2Cl2] PTSA
Pd(TFA)2
[Pd2(dba)3]
Pd/C
78 (95:5)
1 (99:1)
10 (91:9)
10 (97:3)
0 (N.D)
9
10
11
12
13
PTSA
PTSA
PTSA
16 (96:4)
0 (N.D)
[a] Reaction conditions: 1a (1 mmol), “CH2O” monomer (6.7 mmol),
[Pd] (1 mol%), dtbpx (4 mol%), acid (4 mol%) in 2 mL of methanol (2a)
at 1008C for 20 h. Yields determined by GC analysis. l/b=linear/
branched. N.D.=not determined. cod=1,5-cyclooctadiene, PTSA=p-
toluenesulfonic acid, MSA=methanesulfonic acid, TFA=trifluoroace-
tate acid, dba=dibenzylideneacetone.
Then, the effects of the amounts of ligand and acid co-
catalyst were investigated using Pd(OAc)2 as the catalyst
precursor. Remarkably, both the the concentration of the
acidic co-catalyst PTSA and the ligand have a profound
influence on the yield of 3a. To our delight, the desired
product is obtained in 96% yield under optimized conditions
(Table 2, entry 3). Notably, higher loadings of the co-catalyst
suppressed the reaction efficiency (Table 2, entries 4 and 5).
Similarly, an excess of dtbpx with respect to PTSA completely
inhibited this transformation (Table 2, entries 2 and 6).
To gain further insights into this reaction, 13C isotope
labeling experiments were implemented (Scheme 2). When
Table 2: Effect of ligand and acid co-catalyst on the methoxycarbonyla-
tion of 1a.[a]
Entry
X
Y
Yield 3a [%] (l/b)
Yield 4a [%]
1
2
3
4
5
6
7
8
4
4
4
4
4
5
2
2
4
3
5
6
8
4
2
4
78 (95:5)
0 (N.D)
96 (95:5)
68 (95:5)
64 (95:5)
0 (N.D)
22
97
4
38
36
100
92
74
0 (N.D)
17 (96:4)
[a] Reaction conditions: 1a (1 mmol), (CH2O)n (200 mg, 6.7 mmol of
-CH2O), Pd(OAc)2 (1 mol%), dtbpx (X mol%), PTSA (Y mol%) in 2 mL
of methanol (2a) at 1008C for 20 h. Yields determined by GC analysis.
2
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Based on the experimental findings, a reaction
mechanism incorporating synchronous quadruple
catalytic cycles is proposed (Scheme 4). It is known
that a PdII catalyst precursor can be reduced in situ to
Pd0 species V in the presence of excess phosphine
ligands.[18] Under acidic conditions, Pd0 complex V is
in an equilibrium with PdII hydride complex I,[19]
which is the key catalytically active species to initiate
the methoxycarbonylation cycle a. Subsequent inser-
tions of alkene 1 and CO followed by alcoholysis of
the acyl PdII complex IV form ester 3 and regenerate
the Pd hydride species I. The CO consumed in cycle
a was produced from catalytic cycle b. More
specifically, at elevated temperature paraformalde-
Scheme 2. 13C Isotope labeling experiments and control experiments using other
alcohols.
13C-labeled paraformaldehyde was applied in this
transformation, surprisingly only 51% of the ester
product was 13C-labeled methyl nonanoate 3aꢀ
along with 49% nonlabeled product 3a
[Scheme 2, Eq. (1)]. In addition, a similar distri-
bution of the 13C-labeled methoxycarbonylation
product was observed for the reaction using
13CH3OH as the solvent [Scheme 2, Eq. (2)].
These results indicate that both formaldehyde
and methanol act as the carbonyl source in this
process simultaneously. Apparently, CO release
from methanol proceeds by sequential dehydro-
genation and decarbonylation processes.[17]
Actually, palladium-catalyzed alcohol dehydro-
genation under such acidic conditions is rather
unusual but it also takes place with other alcohols
under these standard conditions. Interestingly,
methyl nonanoate (3a) and isopropyl nonanoate
(5) were both produced in the reaction of
isopropanol [Scheme 2, Eq. (3)]. This demon-
strates that under our catalytic conditions meth-
anol is also generated from formaldehyde through
transfer hydrogenation with isopropanol.
Encouraged by the hydrogenation/dehydro-
genation reactivity of this catalytic system, we
wondered if methanol or paraformaldehyde alone
could act as both the CO surrogate and nucleo-
phile for the methoxcarbonylation reaction.
Unfortunately, no desired product was attained
(Scheme 3). This finding illustrates that methanol
dehydrogenation occurs only in the presence of
Scheme 4. Proposed reaction mechanism: Quadruple catalytic cycles.
formaldehyde as the hydrogen acceptor.
hyde can depolymerize to produce formaldehyde,
which will undergo an oxidative addition with Pd0
species V to generate the (hydrido)(acyl)palladium(II)
complex VI. Upon decarbonylation, this latter complex
provides PdII dihydride complex VII and releases CO
gas for the methoxycarbonylation process. The reduc-
tive elimination of VII regenerates Pd0 catalyst V and
produces hydrogen. Meanwhile, the dehydrogenation
of methanol (2a) is also catalyzed by PdII hydride I to
afford formaldehyde through catalytic cycle c. In this
cycle, the coordination of methanol to complex I
Scheme 3. Methoxycarbonylation of 1a using only (CH2O)n or MeOH (2a).
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Table 3: Pd-catalyzed methoxycarbonylation of alkenes 1 with paraformaldehyde and methanol (2a).[a]
Entry Substrate 1
Product 3[b]
Yield 3 [%] (l/b)[c]
Entry Substrate 1
Product 3[b]
Yield 3 [%] (l/b)[c]
1
93 (95:5)
10
58, 8 h[e]
2
93 (94:6)
11
75, 36 h[e]
3
4
75 (89:11)
92 (95:5)
12
13
76 (>99:1)
69 (>99:1)
5[d]
99
14
15
43 (>99:1)
73 (>99:1)
6
85 (>99:1)
7
55 (>99:1)
16
17
92 (>99:1)
8
9
89 (>99:1)
86 (94:6)
90 (78:22)
[a] Reaction conditions: 1 (1 mmol). (CH2O)n (200 mg, 6.7 mmol of -CH2O), Pd(OAc)2 (1 mol%), dtbpx (4 mol%), PTSA (5 mol%) in 2 mL of
methanol (2a) at 1008C for 20 h. [b] The main isomer of a mixture of methyl ester products is shown. [c] Yield of isolated product for a mixture of
methyl ester isomers. [d] See the Supportorting Information for detail conditions. [e] Reaction time.
provides (hydrido)(methoxy)palladium(II) species VIII,
which gives PdII dihydride complex VII by b-hydride elimi-
nation. Finally, intermediate VII undergoes reductive elimi-
nation and oxidative addition with HX to close this catalytic
cycle and also liberate hydrogen. Simultaneously, formalde-
hyde can enter catalytic cycle d, which is the reverse process
of cycle c. Accordingly, an equilibrium between methanol and
formaldehyde is established through these two palladium-
catalyzed processes.
With the optimized reaction conditions in hand, we
continued to probe the scope of alkenes 1 for the Pd-
catalyzed methoxycarbonylation reaction with paraformalde-
hyde and methanol (2a; Table 3). The reactions of terminal
aliphatic alkenes such as 1-octene (1a) and 1-decene (1d)
were very efficient with > 90% yields and up to 95% n-
selectivity (Table 3, entries 1 and 4). More significantly,
mixtures of internal and terminal olefins are usually preferred
as less expensive start materials in industrial manufacture.
Therefore, double-bond isomerization followed by carbon-
ylation process is of great industrial interest. Delightfully, this
catalytic system was able to convert aliphatic internal olefins
including 2-octene and 4-octene into the corresponding linear
methyl nonanoate with high yield and n-selectivity (Table 3,
entries 2 and 3). Moreover, a more-stable internal conjugated
ester underwent the same isomerization/methoxycarbonyla-
tion transformation as well to provide industrially essential
dimethyl glutarate (3n) in 92% yield and up to over 99% n-
selectivity (Table 3, entry 16).
Terminal functionalization of fatty acids is another
synthetic challenge. The isomerizing methoxycarbonylation
of renewable methyl oleate (1p) again proceeded smoothly
under optimized conditions and led to the selective formation
of the respective linear diester product (Table 3, entry 17).
Methyl propionate (3c) was obtained in 99% yield using
ethylene (1e) as the substrate with a TON of 536 for the
palladium catalyst (Table 3, entry 5).
4
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Keywords: carbonylation · CO surrogates · formaldehyde ·
methanol · palladium
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Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Carbonylation
Q. Liu, K. Yuan, P. Arockiam, R. Franke,
H. Doucet, R. Jackstell,
M. Beller*
&&&& — &&&&
Regioselective Pd-Catalyzed
CO-llaboration: An efficient synthetic
carbonylation without the utilization of
hazardous CO gas is described. For the
first time, highly regioselective methoxy-
carbonylation using paraformaldehyde
and methanol as carbonyl sources pro-
ceeds in the presence of a suitable palla-
dium catalyst. This provides a green and
atom-efficient process for the synthesis of
methyl esters in high yield and regiose-
lectivity.
Methoxycarbonylation of Alkenes Using
both Paraformaldehyde and Methanol as
CO Surrogates
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!