Simultaneous control of regioselectivity and enantioselectivity in the hydroxycarbonylation and methoxycarbonylation of vinyl arenes

Article abstract of DOI:10.1039/c3cc41291a

Using a family of novel mononuclear and dinuclear palladium complexes of phanephos ligands, the simultaneous control of regioselectivity and enantioselectivity in the hydroxycarbonylation and alkoxycarbonylation of styrene derivatives has been realised for the first time. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc41291a

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Simultaneous control of regioselectivity and
enantioselectivity in the hydroxycarbonylation
and methoxycarbonylation of vinyl arenes†
Tina M. Konrad,a Jamie T. Durrani,a Christopher J. Cobleyb and Matthew L. Clarke*a
Cite this: Chem. Commun., 2013,
49, 3306
Received 19th February 2013,
Accepted 4th March 2013
DOI: 10.1039/c3cc41291a
www.rsc.org/chemcomm
Using a family of novel mononuclear and dinuclear palladium chiral catalysts in these studies gave 30% ee or less with a b : l of
complexes of phanephos ligands, the simultaneous control of 2 : 1 (or less) in methoxycarbonylation of styrene.4a
regioselectivity and enantioselectivity in the hydroxycarbonylation
We recently discovered that Pd complexes of the Phanephos
and alkoxycarbonylation of styrene derivatives has been realised ligands gave high enantioselectivity in these reactions (up to
for the first time.
95% ee for norbornene; 80% ee for styrene).5 None-the-less,
even these catalysts did not control regioselectivity in the
Chiral carboxylic acids are key building blocks for the synthesis hydroxycarbonylation of styrene. Since this class of reaction
of chiral drugs and natural products. To be viable at larger and the Phanephos ligands6 have been proven to be adaptable
scale, a synthesis of enantiomerically enriched small molecules to commercial production, we have initiated a project aiming to
needs to use cheap reagents. Hydroxycarbonylation is a reac- transform these promising initial findings into a synthetically
tion that converts a generally cheap class of starting material useful catalyst. Here we show that new phanephos ligands
(an alkene) into an acid, using two of the cheapest chemicals generate catalysts that display exquisite control of regioselectivity
known: water and carbon monoxide; in an idealised case there while maintaining good levels of enantioselectivity in both hydroxy-
are no by-products.1,2 There are several processes to produce carbonylation and methoxycarbonylation of styrenes.
achiral or racemic acids (or esters by alkoxycarbonylation) at
large scale.
Before embarking on a programme of making new catalysts,
a range of other reaction variables were investigated for the
Since the birth of asymmetric catalysis, attempts have been hydroxycarbonylation of styrene using the Xyl-Phanephos–Pd
made to realise alkene carbonylation enantioselectively. system. These results are archived in the ESI† and can be
Although some excellent research has helped understand the simply summarised; the dipalladium species outperforms the
nature of this reaction, until recently enantioselective hydroxy- monomeric catalysts significantly in terms of productivity, an
carbonylation of the model substrate styrene always gave near acid at least as strong as trifluoroacetic acid is needed, and
racemic products, often with no control of regioselectivity and chloride is required for the higher enantioselectivity. Under any
unfavourable reaction conditions.3 Enantioselective methoxy- conditions examined, the regioselectivity is quite close to 1 : 1.
carbonylation of styrene has recorded better results, but none A range of new Phanephos–Pd catalysts were therefore prepared
are really synthetically useful and the use of high temperatures (Scheme 1 and ESI†).
with >1 equivalents of acid cocatalyst is common.4 In general
The ligands were either prepared using commercially available
monophosphines do control regioselectivity, but give low ee, chlorophosphines or from the known precursor bis-dichloro-
while diphosphines give mainly linear products. A few papers phosphine paracyclophane6e The choice of meta-substitution
report on branched-selective alkoxy-carbonylation of styrene patterns stemmed from repeatedly finding better results with
with diphosphine species with electron deficient or bulky meta-xylyl-Phanephos relative to Ph-Phanephos in our prior
phosphorus centres;1h,2c,h,4a these show that this type of modi- studies. The procedures reported reproducibly gave crude
fication can improve branched selectivity. However, the only ligands of high purity, that were then fully purified in workable
yields. The monomeric complexes are readily prepared in pure
a School of Chemistry, University of St Andrews, EaStCHEM, St Andrews, Fife, UK.
E-mail: mc28@st-andrews.ac.uk; Fax: +44 (0)1334 463808;
Tel: +44 (0)1334 463850
b Chirotech Technology Ltd. Dr Reddys Laboratories (EU) Limited,
410 Cambridge Science Park, Milton road, Cambridge, UK CB4 0PE
† Electronic supplementary information (ESI) available: Full experimental details
and analytical data. See DOI: 10.1039/c3cc41291a
form. If these are treated with one further equivalent of
[PdCl2(PhCN)2], then immediate formation of the dipalladium
species was observed, or the dipalladium complexes are more
conveniently prepared from two equivalents of [PdCl2(PhCN)2].
Some of the dipalladium complexes have sparing solubility,
and complex 3di was completely insoluble in common solvents,
c
3306 Chem. Commun., 2013, 49, 3306--3308
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Table 1 Ligand screening reveals the incredibly pronounced ligand-electronic
effects on the regioselectivity and enantioselectivity in the hydroxycarbonylation
of styrene
Entrya
Catalyst
Time (h)
% Acidb {yield}
B/Lb
0.8
eec,d
%
1
2
3
4
5
6
7
8
1mo
1di
2mo
2di
3mo
3di
4mo
4di
5mo
5di
6mo
6di
7mo
7di
42
42
42
42
20
20
20
20
20
20
24
19
24
24
4
35
8
71
10
7
98
>99
38
>99
44 {40}
90 {82}
97 {91}
>99 {94}
62
69
50
80
25
48e
50
55
69
53
54
77
60
65
1.1
0.4
1.1
1.7
3.0
6.0
16
2.9
4.2
9
10
11
12
13
14
48
>100
20
29
a
Reactions were carried out according to table, equation and ESI unless
stated otherwise. % Product determined against 1-methylnaphthalene
internal standard using 1H-NMR spectroscopy. B/L ratio determined
b
by 1H NMR. Conversion of alkene is identical or very similar to
production of acid quoted. Yields in { } refer to yield of pure acid isolated
Scheme 1 Synthesis of Phanephos ligands and their mononuclear and dinuclear
palladium complexes. (S)-Phanephos derivatives are shown above, but in some
cases both enantiomers were prepared.
c
after acid–base extraction. Enantiomeric excess determined by chiral
HPLC. (R)-catalysts give (R) product and vice versa. Dipalladium
species formed from monomer in situ.
d
e
possibly influencing its performance in catalysis. A family of
14 Phanephos-derived catalysts were available to test in the
carbonylations. All the complexes are air stable for extended
periods of time, and as testified by the catalytic application in
water, are tolerant of moisture.
The new catalysts were then investigated in the enantio-
selective hydroxycarbonylation of styrene (Table 1 and Table S1,
ESI†). It can be seen from Table 1 that all of the new function-
alised catalysts give enhanced regioselectivity in hydroxy-
carbonylation relative to the parent Ph-Phanephos system.
The results strongly suggest that steric bulk and electronegative
substituents both have a separate positive effect on the
branched regioselectivity.
The alkoxycarbonylation of alkenes is also a potentially
important reaction, since it produces esters in a single step
without coupling agents. All the new catalysts were examined in
methoxycarbonylation of styrene as a model reaction. A full
table showing all the pre-catalysts under a variety of conditions
can be found in the ESI.† Scheme 2 shows the most useful
results. We were delighted to find that 6di delivers high yields
Table
2
Enantioselective and regioselective hydroxycarbonylation of some
other vinyl arenes
The most regioselective catalyst, which gave essentially a
single regioisomer, was the dipalladium complex derived from
the most electron withdrawing ligand, L6. This catalyst achieves
similar ee values as the Xyl-Phanephos dipalladium catalyst, and is
also more reactive than 2di. The somewhat insoluble catalysts
derived from the bulkiest ligand, L3 displays relatively poor activity
in these reactions and while some ligands display very significant
improvements if introduced as a dipalladium species, this is not the
case for the insoluble 3di. Extension of the reaction to some other
vinyl arenes was carried out with (R)-6di. This was successful
although slight variations in the reaction conditions were required.
It may be worth noting that the more electron donating alkene gives
R group in
substrate
% Acida
[yield]
Entry
T (1C)
Time (h)
B/Lb
eec,d
1
2
3
4
5
6
7
4-Cl
4-Cl
4-t-Bu
4-CO2H
2-Cl
3-F
4-Ph
70
40
40
50
60
60
60
22
22
22
22
22
22
22
>99 [93]
43
40 [24]
91 [74]
89 [71]
>99 [90]
95 [81]
>100
>100
68
>100
57
95
61
66
75
62
66 (—)
60
73
62
a
Reactions were carried out according to equation and ESI unless
stated otherwise. % Product determined against 1-methylnaphthalene
measureable traces of the linear acid in this reaction, consistent internal standard using 1H-NMR spectroscopy. Yields in [ ] refer to yield
b
of pure acid isolated after acid–base extraction. B/L ratio determined
with reduced levels of electron density on palladium being signifi-
cant in the control of regioselectivity. All of the acid products could
c
by 1H NMR. Enantiomeric excess determined by chiral HPLC.
d
(R)-catalysts give (R) product and vice versa except where sign is given:
be isolated in pure form by simple acid–base extraction (Table 2).
(—) enantiomers are assigned as (R) by analogy.
c
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Notes and references
1 (a) I. del Rio, C. Claver and P. W. N. M. van Leeuwen, Eur. J. Inorg.
Chem., 2001, 2719; (b) H. Neumann, A. Brennfu¨hrer and M. Beller,
Adv. Synth. Catal., 2008, 350, 2437; (c) A. Seayad, S. Jayasree and
R. V. Chaudhari, Org. Lett., 1999, 1, 459; (d) A. Ionescu, G. Laurenczy
and O. F. Wendt, Dalton Trans., 2006, 3934; (e) M. S. Goedheijt,
J. N. H. Reek, P. C. J. Kamer and P. W. N. M. Van Leeuwen, Chem.
Commun., 1998, 2431; ( f ) J. J. R. Frew, M. L. Clarke, U. Mayer, H. van
Rensburgh and R. P. Tooze, Dalton Trans., 2008, 1976;
(g) A. Grabulosa, J. A. Fuentes, J. J. R. Frew, A. M. Z. Slawin and
M. L. Clarke, J. Mol. Catal. A: Chem., 2010, 330, 18; (h) J. J. R. Frew,
M. L. Clarke, K. Damian, A. M. Z. Slawin, H. van Rensburgh and
R. P. Tooze, Chem.–Eur. J., 2009, 15, 10504 and ref’s therein.
Scheme 2 The leading catalysts for enantioselective and regioselective methoxy-
carbonylation of styrene. Results from a full catalyst screen can be found in
the ESI.†
2 (a) W. Clegg, G. R. Eastham, M. R. J. Elsegood, R. P. Tooze, X. L. Wang
and K. Whiston, Chem. Commun., 1999, 1877; (b) C. Jimenez
Rodriguez, D. F. Foster, G. R. Eastham and D. J. Cole-Hamilton,
Chem. Commun., 2004, 1720. For related processes: (c) H. Ooka,
T. Inoue, S. Itsuno and M. Tanaka, Chem. Commun., 2005, 1173;
(d) R. I. Pugh, E. Drent and P. G. Pringle, Chem. Commun., 2001, 1476;
(e) J. A. Fuentes, A. M. Z. Slawin and M. L. Clarke, Catal. Sci. Technol.,
2012, 2, 715; ( f ) T. Fanjul, G. Eastham, M. F. Haddow, A. Hamilton,
P. G. Pringle, A. G. Orpen, T. P. W. Turner and M. Waugh, Catal. Sci.
Technol., 2012, 2, 937; (g) V. de la Fuente, M. Waugh, G. R. Eastham,
J. a. Iggo, S. Castillon and C. Claver, Chem.–Eur. J., 2010, 16, 6919;
of an essentially regiochemically pure branched ester with
similarly good enantioselectivity as it does in hydroxycarbonyl-
ation, providing methanol is used as a reagent (2.5 equiv.),
rather than solvent. The catalysts derived from ligand L4 also
show very different behaviour in neat methanol to using a small
excess (ESI†), with quite respectable 93% regioselectivity and
4 : 1 ratio of enantiomers (Scheme 2). The bulky ligand L3,
which gave very poor catalysts in styrene hydroxycarbonylation,
gives good reactivity near room temperature using 0.5% catalyst,
reasonable control of regioselectivity (80%) and over 20: 1 ratio
of enantiomers. In this case, the more soluble monomeric
catalyst is slightly more active than the (less soluble) dimer
and the performance of the former is shown in Scheme 2.
A range of mono- and dinuclear palladium complexes of a
family of Phanephos ligands have been prepared. Investigating
this group of catalysts in the hydroxycarbonylation and
methoxycarbonylation of styrene and a few of it’s derivatives
has uncovered a remarkable improvement in regioselectivity
from around 1 : 1 in the parent Ph-substituted system to over
100 : 1. While the results referred to in the literature enabled us
to predict some increase in branched selectivity using the
fluorinated ligands, the ability to tune from 1 : 1 to essentially
perfect regioselectivity, whilst retaining decent levels of enantio-
selectivity is completely unexpected. The parent system, 2di
while giving good enantioselectivity delivers less than 50% yield
of the desired enantiomer once conversion, regioselectivity and
ee are taken into account, but 6di produces around 90%
enantiomer yield in these reactions, not too dissimilar from
the best examples of enantioselective hydroformylation.7 It is
therefore hoped that asymmetric hydroxy- and methoxy-
carbonylation of alkenes may be capable of becoming a practical
reaction for scaleable asymmetric synthesis. Mechanistic
studies, catalyst recycling, further optimisation of catalysts,
and new synthetic applications seem to be the most pressing
topics to be dealt with and investigations are underway.
JTD and TMK are joint major contributors to this research
project. The authors thank Chirotech-Dr Reddys Laboratories
and the European Union ITN, NANOHOST for funding.
The contributions of the St Andrews technical staff and the
EPSRC National Mass spectrometry Service are gratefully
acknowledged.
¨
(h) L. Diab, M. Gouygou, E. Manoury, P. Kalck and M. Urrutigoıty,
Tetrahedron Lett., 2008, 49, 5186.
3 (a) I. del Rio, N. Ruiz, C. Claver, L. A. van der Veen and P. W. N. M. van
Leeuwen, J. Mol. Catal. A: Chem., 2000, 161, 39; (b) The selectivity of an
enantioselective carbonylation using chiral phosphonic acid ligands
seems to be difficult to reproduce and transfer to related reactions
(H. Alper, personal communication). Other problems that preclude
application are the use of >10% catalyst along with 3 promoters
(CuCl2, HCl and oxygen); H. Alper and N. Hamel, J. Am. Chem. Soc.,
1990, 112, 2803; (c) 8–38% ee was realised in alkoxycarbonylations
using the same system: Y. Kewu and J. Zuanzhen, Chem. J. Internet,
´
2005, 7, 14; (d) M. Dolors Miqual-Serrano, A. Aghmiz, M. Dieguez,
´
A. M. Madeu-Bulto, C. Claver and D. Sinou, Tetrahedron: Asymmetry,
1999, 10, 4463; (e) K. Damian and M. L. Clarke, unpublished results.
˜
4 (a) E. Guiu, M. Caporali, B. Munoz, C. Muller, M. Lutz, A. L. Spek,
C. Claver and P. W. N. M. Van Leeuwen, Organometallics, 2006,
25, 3102; (b) C. Goddard, A. Ruiz and C. Claver, Helv. Chim. Acta,
2006, 89, 1610; (c) I. del Rio, N. Ruiz and C. Claver, Inorg. Chem.
˜
Commun., 2000, 3, 166; (d) B. Munoz, A. Marinetti, A. Ruiz, S. Castillon
and C. Claver, Inorg. Chem. Commun., 2005, 8, 1113; (e) S. Oi,
M. Nomura, T. Aiko and Y. Inoue, J. Mol. Catal. A: Chem., 1997,
115, 289; ( f ) G. Cometti and G. P. Chiousoli, J. Organomet. Chem.,
1982, 236, C31; (g) B. C. Zhu and X. Z. Jiang, Appl. Organomet. Chem.,
´
2006, 20, 277; (h) C. Blanco, A. Ruiz, C. Godard, N. Fleury-Bregeot,
A. Marinetti and C. Claver, Adv. Synth. Catal., 2009, 351, 1813.
5 (a) T. M. Konrad, J. A. Fuentes, A. M. Z. Slawin and M. L. Clarke,
Angew. Chem., Int. Ed., 2010, 49, 9197; (b) M. L. Clarke and
T. M. Konrad, WO2011030110, University of St Andrews, 2009.
6 (a) P. J. Pye, K. Rossen, R. A. Reamer, N. N. Tsou, R. P. Volante and
P. J. Reider, J. Am. Chem. Soc., 1997, 119, 6207; (b) P. J. Pye, K. Rossen,
R. A. Reamer, R. P. Volante and P. J. Reider, Tetrahedron Lett., 1998,
39, 4441; (c) M. J. Burk, W. Hems, D. Herzberg, Ch. Malan and A. Zanotti-
Gerosa, Org. Lett., 2000, 2, 4173; (d) B. Dominguez, A. Zanotti-Gerosa and
W. Hems, Org. Lett., 2004, 6, 1927; (e) A. Zanotti-Gerosa, Ch. Malan and
D. Herzberg, Org. Lett., 2001, 3, 3687.
7 Some of the most regioselective enantioselective hydroformylation
catalysts for styrene and related substrates: (a) T. P. Clark,
C. R. Landis, S. L. Freed, J. Klosin and K. A. Abboud, J. Am. Chem.
Soc., 2004, 127, 5040; (b) G. M. Noonan, J. A. Fuentes, C. J. Cobley and
M. L. Clarke, Angew. Chem., Int. Ed., 2012, 51, 2477 (see also
WO2012016147); (c) A. T. Axtell, C. J. Cobley, J. Klosin, G. T.
Whiteker, A. Zanotti-Gerosa and K. A. Abboud, Angew. Chem., Int.
Ed., 2005, 44, 5834; (d) N. Sakai, S. Mano, K. Nozaki and H. Takaya,
J. Am. Chem. Soc., 1993, 115, 7033.
c
3308 Chem. Commun., 2013, 49, 3306--3308
This journal is The Royal Society of Chemistry 2013