Highly enantioselective hydroxycarbonylation and alkoxycarbonylation of alkenes using dipalladium complexes as precatalysts

Article abstract of DOI:10.1002/anie.201004415

Joined at Pd: Novel palladium catalysts like 1, in which the planar-chiral phosphine acts as a bridging ligand, have been developed. These dimetallic complexes are highly enantioselective catalysts in the hydroxycarbonylation of alkenes, a reaction that has proven problematic over the years. PTSA=para-toluenesulfonic acid. Copyright

Full text of DOI:10.1002/anie.201004415

Angewandte
Chemie
DOI: 10.1002/anie.201004415
Enantioselective Carbonylation
Highly Enantioselective Hydroxycarbonylation and
Alkoxycarbonylation of Alkenes using Dipalladium Complexes as
Precatalysts**
Tina M. Konrad, Josꢀ A. Fuentes, Alexandra M. Z. Slawin, and Matthew L. Clarke*
Carboxylic acids make up a significant proportion of the
commercially available chiral building blocks. An optimized
process that produces enantioenriched carboxylic acids from
readily available, cheap chemicals without the need for
resolution is highly desired. One of the more important
developments in catalysis in recent years has been the
development of palladium catalyzed carbonylation of ethyl-
ene into a large scale highly productive commercial process
for the formation of methyl propionate.[1] An enantioselective
variant of alkene carbonylation is potentially the most
efficient and versatile method to make single-enantiomer
carboxylic acid derivatives, and both hydroxycarbonylation[2]
and methoxycarbonylation[3] have attracted attention for
many years.
operates well below 1008C, uses less than 1 equivalent of an
acid promoter, and delivers product with up to 95% ee. In
addition, it makes use of a class of precatalysts, namely
dimetallic halides derived from chiral bridging diphosphines,
that are unexplored not only in carbonylation reactions but in
any form of asymmetric catalysis.[5]
In the course of preparing a series of simple monomeric
palladium complexes of the type [PdCl2(L)] (L = ligand) from
the planar chiral phanephos ligands 1 and 2 (Scheme 1), we
The majority of studies have specifically focused on
methoxycarbonylation (also referred to as hydroesterifica-
tion) of styrene. Important contributions to this field include
some reports of very good enantioselectivity.[3] However, the
reaction has not been widely used in synthesis because of the
high reaction temperatures (ca. 1508C), greater than stoi-
chiometric amount of acid co-catalysts, and the low overall
yield of the branched acid. Enantioselective hydroxycarbo-
nylation has been very problematic indeed, and a large
improvement in catalyst performance is required before it can
be considered a synthetically useful process.[4]
We have undertaken studies to improve substrate scope
and regiochemical control of the reaction,[2f,g,j] but our
ambition has always been to realize a useful enantioselective
process. For a number of years, this ambition has been
thwarted by even the very best chiral diphosphine ligands
giving mediocre enantioselectivities, as has been found by
others; the best diphosphine reported in the literature gave
only 43% ee, and most ligands give near-racemic products.[4]
Herein we show a highly enantioselective process that
Scheme 1. Synthesis of monomeric and dimetallic palladium com-
plexes using the phanephos ligands 1 and 2.
observed unexpected side-products (1di,2di). Additional
investigation using combustion analysis and mass spectrom-
etry suggested this side-product to be a dimetallic complex in
which the chiral diphosphine bridges two palladium centers.
For the well-known phanephos ligands 1 and 2, either
dipalladium (1di,2di) or monopalladium (1mo,2mo) com-
plexes can be prepared in high yield by employing the
appropriate stoichiometry.
Halide-bridged palladium dimers are well-known species
in cases where each metal is bound by one monophosphine
such as triphenylphosphine.[6a] However, halide-bridged
dipalladium complexes in which a diphosphine also forms a
bridge between the two metals are very rare,[6b–d] and this is
seemingly the first example using an enantiomerically pure
diphosphine.
[*] T. M. Konrad, Dr. J. A. Fuentes, Prof. A. M. Z. Slawin, Dr. M. L. Clarke
School of Chemistry, University of St Andrews,
EaStCHEM
St Andrews, Fife, Scotland (UK)
Fax: (+44)1334-463808
E-mail: mc28@st-andrews.ac.uk
[**] We thank the University of St Andrews and the European Union ITN,
Nanohost for financial support (T.M.K.), and Dr. Reddys CPS-
Chirotech for a grant to develop this technology. We thank Dr. Chris
Cobley (Dr. Reddys CPS-Chirotech) for fruitful discussions.
Technical support at the University of St Andrews is also gratefully
acknowledged.
Diphosphines are normally employed in excess in alkene
carbonylation, and the successful use of diphosphines in
thousands of different enantioselective reactions has relied
upon them adopting a stable chelate coordination mode.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004415.
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Table 2: Enantioselective methoxycarbonylation of styrene.
Nonetheless, the performances of the dipalladium complexes
Entry[a]
Catalyst
T [8C]
t [h]
Ester [%][b]
b/l[c]
ee [%][d]
1di and 2di in the hydroxycarbonylation of styrene were
compared to their monomeric counterparts (Table 1). At
1
2
3
4
5
6
7
8
9
10
1di
1mo
2di
2mo
1di
1mo
2di
2mo
2di
2di
50
50
50
50
50
50
50
50
35
25
42
42
42
42
3
3
3
3
67
42
>99
95
>99 (66)
>99
10
3
17
18
>99
71 (62)
0.43
0.34
0.57
0.12
0.57
0.71
0.86
0.69
0.88
0.95
69
72
80
80
54
69
79
80
89
91
Table 1: Enantioselective hydroxycarbonylation of styrene.
Entry[a]
Catalyst
T [8C]
t [h]
Yield [%][b]
b/l[c]
ee [%][d]
[a] Reactions conditions: catalyst (1 mol%), styrene (1 mmol), CO
(30 bar), methanol (1.5 mL), LiCl (20 mol%), and p-toluene sulfonic
acid hydrate co-catalyst (20 mol%). [b] Determined by NMR analysis
using an internal standard (see the Supporting Information). Value in
parentheses is the yield of the pure ester isolated after column
chromatography. [c] The b/l ratio was determined by 1H NMR spectros-
1
2
3
4
5
6
7
8
1di
1mo
2di
2mo
1di
1mo
2di
2mo
2di
2mo
1di
100
100
100
100
60
60
60
60
50
18
18
17
17
17
17
16
17
42
42
42
42
53
51
67
60
29
4
58
14
71
8
0.68
0.28
0.30
0.25
1.2
1.2
1.0
0.73
1.1
0.43
1.1
18
8
18
16
59
55
76
66
80
50
69
62
copy. [d] Determined by HPLC analysis using
R-configured catalysts gives R-configured product and vice versa.
a chiral column.
9
10
11
12
50
50
50
35
4
in the Supporting Information). The methoxycarbonylations
still proceed well at temperatures as low as 258C, which
allows even higher enantioselectivity to be realized (Table 2,
entry 10). In the literature, alkoxycarbonylations are reported
to proceed with much better enantioselectivity than hydrox-
ycarbonylations. However, by using these dimetallic catalysts,
the results in terms of enantioselectivity at a given temper-
ature are similar to those of hydroxycarbonylation reaction,
even though the activity is higher for all catalysts. This
similarity is consistent with some aspects of the mechanism
being common to both processes.
1mo
0.75
[a] Reactions conditions: catalyst (1 mol%), styrene (1 mmol), water
(2.5 mmol), CO (30 bar), of degassed butanone as solvent (1.5 mL), LiCl
(20 mol%), and p-toluene sulfonic acid hydrate co-catalyst (PTSA;
20 mol%). [b] Yield of pure acid isolated after an acid/base extraction of
the crude reaction mixture. [c] The branched to linear (b/l) ratio was
determined by using 1H NMR spectroscopy. [d] Determined by HPLC
analysis using a chiral column. R-configured catalysts give R-configured
product and vice versa.
temperatures above 1008C, the products were nearly racemic,
but we were encouraged by the quite reasonable reactivity. To
our surprise, reducing reaction temperatures enabled the first
reasonably efficient enantioselective hydroxycarbonylation.
The dipalladium precatalysts reproducibly gave higher reac-
tivity and comparable or even slightly higher enantioselec-
tivity than their monomeric analogues. When using styrene as
the substrate, the expected mixture of regioisomers was
formed, but up to 81% ee can be realized at around 508C
when using 20 mol% of the acid co-catalyst (Table 1 and
Tables S1 and S2 in the Supporting Information). Para-tert-
butylstyrene also underwent hydroxycarbonylation in good
yield and with 85% ee. Markedly improved results were once
again seen using the dipalladium complexes as precatalysts
(Table S2 in the Supporting Information)
Our studies show that similar ee values can be realized in
enantioselective methoxycarbonylation of styrene at a given
temperature, suggesting that the new catalysts will prove
useful for this class of reaction. For example, Table 2 shows
the methoxycarbonylation of styrene in the presence of 1di
and 2di by using similar reaction conditions to those used for
the hydroxycarbonylation; however, methanol was used as
both a reagent and solvent. The methoxycarbonylation
reaction is more facile as the catalysts perform competently
at 508C; shorter reaction times or dilution indicate that the
dimers have higher activity (Table 2, entries 5–8 and Table S4
Despite operating at lower temperatures than has been
generally reported in the literature, we have utilized similar
catalyst loadings relative to those of previous reports
(ca. 1 mol%) and the methoxycarbonylation proceeds well
with just 0.09 mol% catalyst (Table S4 in the Supporting
Information). This family of catalysts are possible candidates
for future development for commercial application. Addi-
tional optimization of the catalyst performance or a recycling
protocol would be useful improvements, and are a part of our
current and future investigations. Another area of develop-
ment in alkoxycarbonylation would be to define a general
protocol for converting most alcohols into esters having high
ee values. To address this issue, we have found that both
nPrOH and iPrOH can be used as nucleophiles to generate
the n-propyl and isopropyl esters, respectively, in good
enantioselectivity (Table S4 in the Supporting Information).
The difference in the product yield for the n-propyl ester
when using 1mo versus 2di was 94%.
The regioisomeric product mixtures are almost always
produced by the diphosphine catalysts and present an area for
improvement in styrene carbonylation; in contrast many
other alkene substrates that give more useful chiral acid
products either do not present regiochemical issues or may
have a different regiochemical bias in carbonylation chemis-
try. However, very little information is known about how
different alkenes behave in hydroxy-carbonylation reactions;
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our next objective was to investigate if enantioselectivity
could be realized on a very different alkene substrate.
We chose to investigate hydroxycarbonyation of norbor-
nene using the dimeric catalysts. The control of the chemo-
selectivity using norbornene is a challenge, and this control
must be accomplished in addition to control of exo/endo
selectivity and enantioselectivity. During the course of our
work, the first promising results for formation of racemic
methyl exo norbornate, as well as an asymmetric synthesis
(40% ee) were published.[7] However, a successful hydrox-
ycarbonylation protocol has not yet been developed.
Our early attempts with norbornene were plagued by
poor chemoselectivity and the formation of low molecular
weight oligomers, thus reducing the selectivity of the reaction.
This problem was also found when using triphenylphosphine-
based catalysts. After some optimization, the new chiral
catalysts delivered high conversion, reasonable chemoselec-
tivity (50 to 65%), high exo/endo selectivity, and up to 95% ee
in the hydroxycarbonylation of norbornene (Scheme 2 and
Figure 1. X-ray structure of complex 2di.
somehow accessed more readily from the dipalladium pre-
catalysts. If the dipalladium complexes form a monomeric
catalyst, then it seems likely that some form of “PdX2” would
be released presumably in a soluble form since the reactions
are homogeneous. An experiment in which the opposite
enantiomer of phanephos was added to the dipalladium
precatalyst was carried out, because it seemed likely that
upon release of “PdX2” the other enantiomer of phanephos
would coordinate to palladium and then deliver a racemic
product. The results showed almost no loss of enantioselec-
tivity in this experiment, but a significant decrease in the yield
(Table S3 in the Supporting Information). The conversion of
the dimer into the active catalyst is therefore rather more
complex, and an intriguing possibility that we cannot rule out
thus far is that the catalytic cycle utilizes dimetallic inter-
mediates having bridging diphosphines. Carbon monoxide,
hydride, and halide ligands are all very competent bridging
ligands that could facilitate this type of cycle. A halide-
bridged dimetallic complex of a monophosphine has been
isolated from a carbonylation experiment, but in this case was
considered to be part of a nonproductive catalytic pathway.[8]
However, given that the monophosphine dimer did promote
the carbonylation in low yield, it is possible that mono-
phosphine dipalladium species are not as long-lived as
diphosphine dipalladium catalysts. Examination of dimetallic
complexes of other chiral bridging phosphines used in other
types of asymmetric catalysis may prove to be an interesting
area for additional study.[5d] It is possible that distinct halide
ligands within the chiral [Pd2Cl2(m-Cl)2] core could be
selectively exchanged for CO and hydride ligands, thereby
making migratory insertion into the alkene complex favored
on one face of the complexed alkene (somewhat reminiscent
of the proposed selective ligand exchanges in the Sharpless
epoxidation using dimeric titanium complexes[9]). Alterna-
tively, given that dual metal systems such as [PdCl2(PPh3)2]
and SnCl2 are enhanced carbonylation catalysts relative to a
mono-metal system, and are postulated to form Pd/SnCl3
species,[10] then it is possible that some form of [PdLxCly] is
released from the dimer, but returns to act as an anionic
ligand for the chiral palladium intermediates at some point in
the cycle, therefore giving the rate enhancements observed. It
is likely that hydrolysis/alcoholysis of the acyl species is the
Scheme 2. An example of one of the first successful hydroxycarbonyla-
tions of norbornene (changing to the S-configured catalyst delivers the
(1S, 2S, 4R)-4 (exo-(2S)-4).
Tables S5 and S6 in the Supporting Information). For this
substrate, both the dipalladium catalysts and monomers give
similar enantioselectivities, and in some cases better reactivity
was encountered using the dipalladium catalysts. The high
enantioselectivity and evidence that the substrate turns over
are very promising for future studies on the applicability of
this class of catalyst.
The use of a precatalyst in which the diphosphine bridges
two metals is extremely rare, and an in-depth study of this
catalyst and its mode of action in carbonylation reaction will
be the focus of future studies. However, to completely
confirm the bimetallic nature of the precatalyst, we have
determined the structure of [Pd2Cl2(m-Cl)2(m-xyl-phanephos)]
using X-ray crystallography. The crystal structure is shown in
Figure 1. Amongst several interesting features, the dimer
possesses a shorter Pd–Pd bond [2.9136(19) ꢀ] than has been
observed in other dimeric palladium halides. The terminal
chloride ligands are located gauche to each other, which is in
contrast to the syn arrangement reported in the study of the
palladium dimers of tritycene diphosphines.[6b] The [Pd2Cl2(m-
Cl)2] core can be best described as possessing an unusual form
of axial chirality, and the mirror image of this core (presum-
ably formed from the opposite enantiomer of diphosphine)
places the terminal chlorines in opposing directions to those
shown in Figure 1.[5c] Our initial working model was that the
real active catalyst would be a monomeric species that is
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Communications
rate-determining step in alkene carbonylation.[2d,h] An experi-
burgh R. P. Tooze, Chem. Eur. J. 2009, 15, 10504; h) D. Milstein,
J. Chem. Soc. Chem. Commun. 1986, 817; i) H. Neumann, A.
Brennfꢂhrer, M. Beller, Adv. Synth. Catal. 2008, 350, 2437; j) A.
Grabulosa, J. J. R. Frew, J. A. Fuentes, A. M. Z. Slawin, M. L.
Clarke, J. Mol. Catal. A 2010, 330, 18.
ment wherein methoxycarbonylation was carried out using
only 3 equivalents of methanol rather than as solvent showed
the monomer to be inactive, under reaction conditions where
the dimer provides 18% product. Thus, it is possible that it is
the methanolysis step that is facilitated by the dimeric
catalyst. Whatever the outcome of the mechanistic studies,
these catalysts enable high enantioselectivity in the hydrox-
ycarbonylation of alkenes, and the reaction is very promising
for the production of chiral acids and esters using inexpensive
starting materials.[11]
[3] a) E. Guiu, M. Caporali, B. Muꢃoz, C. Muller, M. Lutz, A. L.
Spek, C. Claver, P. W. N. M. Van Leeuwen, Organometallics
2006, 25, 3102; b) C. Godard, A. Ruiz, C. Claver, Helv. Chim.
Acta 2006, 89, 1610; c) I. del Rꢁo, N. Ruiz, C. Claver, Inorg.
Chem. Commun. 2000, 3, 166; d) B. Muꢃoz, A. Marinetti, A.
Ruiz, S. Castillon, C. Claver, Inorg. Chem. Commun. 2005, 8,
1113; e) S. Oi, M. Nomura, T. Aiko, Y. Inoue, J. Mol. Catal. A
1997, 115, 289; f) G. Cometti, G. P. Chiousoli, J. Organomet.
Chem. 1982, 236, C31; g) B. C. Zhu, X. Z. Jiang, Appl. Organo-
met. Chem. 2006, 20, 277; h) D. B. G. Williams, M. L. Xhaw, M. J.
Green, C. W. Holzapfel, Angew. Chem. 2008, 120, 570; Angew.
Chem. Int. Ed. 2008, 47, 560.
[4] a) I. del Rio, N. Ruiz, C. Claver, L. A. van der Veen, P. W. N. M.
van Leeuwen, J. Mol. Catal. A 2000, 161, 39; b) A preliminary
report of an enantioselective carbonylation using binaphthyl
phosphoric acid ligands appeared some time ago, but unfortu-
nately yields were moderate and over 10% catalyst was required
along with three promoters (CuCl2, HCl, and oxygen). H. Alper,
N. Hamel, J. Am. Chem. Soc. 1990, 112, 2803; c) Only 8–38% ee
was realized in alkoxycarbonylations using the same system: Y.
Kewu, J. Zuanzhen, Chem. J. Internet 2005, 7, 14; d) M. Dolors
Miquel-Serrano, A. Aghmiz, M. Diꢄguez, A. M. Masdeu-Bultꢅ,
C. Claver, D. Sinou, Tetrahedron: Asymmetry 1999, 10, 4463.
[5] The nearest precedents we have found for dimeric metal halides
of chiral bridging diphosphines are quite far removed: a) Achiral
dimeric hydroformylation catalysts: D. A. Aubry, N. N. Bridges,
K. Ezell, G. G. Stanley, J. Am. Chem. Soc. 2003, 125, 11180;
b) Chiral dipalladium complexes of a special bridging triketo-
nate ligand in asymmetric oxidation: A. K. El-Qisairi, H. A.
Qaseer, P. M. Henry, J. Organomet. Chem. 2002, 656, 168; c) Co-
polymerization catalysts with bridging chiral nitrogen ligands: A.
Scarel, J. Durand, D. Franchi, E. Zangrando, G. Mestroni, C.
Carfagna, L. Mosca, R. Seraglia, G. Consiglio, B. Milani, Chem.
Eur. J. 2005, 11, 6014; d) Chiral bridging ligands in hydro-
genation: F. W. Patureau, S. de Boer, M. Kuil, J. Meeuwissen, P.-
A. R Breuil, M. A. Siegler, A. L. Spek, A. J. Sandee, B. de Bruin,
J. N. H. Reek, J. Am. Chem. Soc. 2009, 131, 6683.
Experimental Section
Additional catalysis experiments, experimental procedures, and
characterization data are available in the Supporting Information.
The X-ray crystal structure data is available from the Cambridge
Crystallographic data Centre; CCDC 783946 contains the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif. The X-ray structure
was determined using MoKa (rotating anode) at 0.71073 ꢀ and 93 K.
Formula: C48H50Cl4P2Pd2; Weight 1043.42; Monoclinic crystals, Space
group P2(1). Unit cell dimensions: a = 9.437(5) ꢀ, b = 17.075(8) ꢀ,
c = 13.627(7) ꢀ. a = 908; b = 100.729(9)8; g = 90; Volume =
2157.6(18) ꢀ3; Density = 1.606 MgmÀ3. 2 formula units per unit cell.
Reflections collected = 21145 (7568 independent reflections).
Rint = 0.1142. R1/wR2 {I > 2s(I)} = 0.0965/0.2909. R1/wR2 (all
data) = 0.1053/0.3010.
Received: July 19, 2010
Published online: October 26, 2010
Keywords: asymmetric catalysis · bridging ligands ·
.
carbonylation · homogeneous catalysis · palladium
[1] a) W. Clegg, G. R. Eastham, M. R. J. Elsegood, R. P. Tooze, X. L.
Wang, K. Whiston, Chem. Commun. 1999, 1877; b) C. Jimenez
Rodriguez, D. F. Foster, G. R. Eastham, D. J. Cole-Hamilton,
Chem. Commun. 2004, 1720; c) For related (also achiral)
processes H. Ooka, T. Inoue, S. Itsuno, M. Tanaka, Chem.
Commun. 2005, 1173; d) R. I. Pugh, E. Drent, P. G. Pringle,
Chem. Commun. 2001, 1476.
[6] a) V. K. Jain, L. Jain, Coord. Chem. Rev. 2005, 249, 3075; b) O.
Grossman, C. Azerraf, D. Gelman, Organometallics 2006, 25,
375; c) C. Azerraf, S. Cohen, D. Gelman, Inorg. Chem. 2006, 45,
7010; d) D. C. Smith, Jr., C. H. Lake, G. M. Gray, Dalton Trans.
2003, 2950.
[2] a) I. del Rꢁo, C. Claver, P. W. N. M. van Leeuwen, Eur. J. Inorg.
Chem. 2001, 2719; b) S. Jayasree, A. Seayad, R. V. Chaudhari,
Chem. Commun. 2000, 1239; c) A. Seayad, S. Jayasree, R. V.
Chaudhari, Org. Lett. 1999, 1, 459; d) A. Ionescu, G. Laurenczy,
O. F. Wendt, Dalton Trans. 2006, 3934; e) M. S. Goedheijt,
J. N. H. Reek, P. C. J. Kamer, P. W. N. M. Van Leeuwen, Chem.
Commun. 1998, 2431; f) J. J. R. Frew, M. L. Clarke, U. Mayer, H.
van Rensburgh R. P. Tooze, Dalton Trans. 2008, 1976; g) J. J. R.
Frew, M. L. Clarke, K. Damian, A. M. Z. Slawin, H. van Rens-
[7] C. Blanco, A. Ruiz, C. Godard, N. Fleury-Brꢄgeot, A. Marinetti,
C. Claver, Adv. Synth. Catal. 2009, 351, 1813.
[8] B. K. Muꢃoz, E. S. Garcia, C. Godard, E. Zangrando, C. Bo, A.
Ruiz, C. Claver, Eur. J. Inorg. Chem. 2008, 4625.
[9] M. G. Finn, K. B. Sharpless, J. Am. Chem. Soc. 1991, 113, 113.
[10] J. F. Knifton, J. Org. Chem. 1976, 41, 2885.
[11] T. M. Konrad and M. L. Clarke (University of St Andrews), PCT
Application 0915946.8, 2009.
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