Rhodium/phospholane-phosphite catalysts give unusually high regioselectivity in the enantioselective hydroformylation of vinyl arenes

Article abstract of DOI:10.1039/c3cc48823c

Using the phospholane-phosphite ligand, BOBPHOS, almost perfect regioselectivities and high enantioselectivities (up to 92% ee) are observed in Rh catalysed enantioselective hydroformylation of vinyl arenes. This can be achieved under solvent-free conditions. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3cc48823c

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Rhodium/phospholane–phosphite catalysts
give unusually high regioselectivity in the
enantioselective hydroformylation of vinyl arenes†
Cite this: Chem. Commun., 2014,
50, 1475
Received 19th November 2013,
Accepted 13th December 2013
Gary M. Noonan,a Christopher J. Cobley,*b Thomas Mahoneyb and
Matthew L. Clarke*a
DOI: 10.1039/c3cc48823c
www.rsc.org/chemcomm
Using the phospholane–phosphite ligand, BOBPHOS, almost perfect
regioselectivities and high enantioselectivities (up to 92% ee) are
observed in Rh catalysed enantioselective hydroformylation of vinyl
arenes. This can be achieved under solvent-free conditions.
Hydroformylation of alkenes is well documented as one of the
most cost- and atom-efficient methods to produce aldehydes.1
A significant number of catalysts offering good to excellent
enantioselectivity in asymmetric hydroformylation have now
appeared, and since the seminal work on BINAPHOS/Rh hydro-
formylation catalysts, phosphine–phosphite ligands2 have been
amongst the most well-studied and proficient ligands for
enantioselective hydroformylation.3 This spurred us to prepare
the hybrid phospholane–phosphite of two of the leading ligands
available for enantioselective hydroformylation: Kelliphite3a,o and
Ph-BPE (Fig. 1).3h The resulting ligand, nicknamed BOBPHOS4
was initially hoped to offer the Best Of Both of these PHOShorus
ligands, since Kelliphite/Rh catalysts display excellent activity
under very mild conditions, even for internal alkenes, and
Ph-BPE/Rh catalysts are very robust and give very good enantio-
selectivities for terminal alkenes such as styrene. Unexpectedly,
Rh/BOBPHOS catalysts were found to favour the formation of
branched aldehydes with high ee from simple terminal alkyl
alkenes: a long standing issue for hydroformylation chemistry,
since these substrates normally favour the linear aldehyde.5
Given that 2-aryl-propanals are important chiral building
blocks, most desirably accessed from cheap vinyl arenes, we
have also studied enantioselective hydroformylation of styrene
and a few of its derivatives using this catalyst. It is worth noting
Fig. 1 Ligands for enantioselective hydroformylation.
that several catalysts from the many published studies have already given good enantioselectivity in this reaction. However,
an issue, as pointed out by Landis,2f is that 5–15% linear aldehyde
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.
E-mail: ccobley@drreddys.com
by-product is often formed. Regioisomer and enantiomer ratios
should be considered equally important in alkene additions,6
so the product of % chemoselectivity, % regioselectivity and
% enantioselectivity (enantiomer ratio): a ‘desired isomer yield’,
is perhaps the best measure of synthetic utility. Using this measure,
only one or two ligands stand out as being directly useful to the
best of our knowledge. For example in styrene hydroformylation,
† Electronic supplementary information (ESI) available: Full experimental details,
further kinetic experiments, NMR and GC spectra. See DOI: 10.1039/c3cc48823c
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the Landis ligands such as (R,R,S)-1 can give desired isomer
yields of 91–94.8% under optimised conditions,2f Ph-BPE up to
94.9%,3h and BINAPHOS up to 82.7% (this can be improved to
90.2% for a derivative with different aryl groups,2b and 86.9% for
a derivative with a P–NH function, Yanphos2i). Here we report
our preliminary findings that show that the Rh/BOBPHOS
catalyst gives excellent performance in the hydroformylation of
vinyl arenes, even under solvent-free conditions.
We initially did some screening experiments in the hydro-
formylation of styrene comparing the (S,S,S) and (S,R,R) isomers
of BOBPHOS at 2 different pressures and temperatures. The
results (Table 1, entries 2 to 5) clearly establish BOBPHOS to give
a ‘desired isomer yield’ (e.g. Table 1, entry 2 = 94.7%) that is
competitive with the best results ever recorded in the many
studies on hydroformylation of styrene. The (S) enantiomer was
formed preferentially: as was the case with alkyl alkenes. Our
alkyl alkene hydroformylation studies used low temperatures
(16 1C) to maintain the high selectivity. However in this case,
selectivity holds up reasonably well at higher temperatures.
A large scale protocol would need lower catalyst loadings, or
a very good recycling protocol, so some reactions were carried
out at low loadings, and a kinetic analysis was carried out
(Fig. 2 and ESI†). We were pleased to find that a reaction at
Fig. 2 Asymmetric hydroformylation of styrene at 3 and 14 bar respectively
and 35 1C. Top: plot of conversion versus time; bottom: plot of T. O. F.
(measured at 0.1 M intervals) versus substrate concentration.
0.05 mol% at 4 M concentration delivered >99% conversion in are both pseudo first order in the alkene substrate, with the
around 4 hours at just 50 1C with a peak T. O. F. of 950 in the T. O. F. dropping evenly as its concentration decreases (Fig. 2).‡
early stages of the reaction. A plot of T. O. F. versus substrate A plot of the natural log of [S] versus time also demonstrates this.
concentration is a convenient graphical way to measure: the On the other hand, the very highly concentrated reaction
initial T. O. F., if catalyst activation is complete when substrate demonstrates kinetics that are in agreement with this being
is added, and to detect if the reactions are diffusion-limited. diffusion limited (see plot of T. O. F. vs. [substrate] in ESI†).
In the low temperature asymmetric hydroformylations at 0.63 M However, as shown in Fig. 2, the asymmetric hydroformylations
concentration, the reactions of styrene, (and 4-chloro-styrene) using the Rh/(S,S,S)-BOBPHOS catalyst are negative order in
syngas, so good rates are still achieved even if limited by solu-
bility of syngas. This, along with the very high desired isomer
yields, the high solubility and robustness of BOBPHOS/Rh
catalysts prompted us to investigate solvent-free hydroformyl-
ation. The solvent in any chemical process is the most significant
contribution to the environmental impact and a significant cost
contributor whether disposed or recycled. It was pleasing to find
that neat styrene can be hydroformylated using 0.025 mol% Rh
pre-catalyst (with no activation) at just 50 1C and 10 bar pressure
to give complete consumption of product within 6 hours, and
maintain the excellent regio-, chemo- and enantioselectivity.
Table 1 Enantioselective hydroformylation of styrene catalysed by Rh/
(S,S,S)-BOBPHOS
Temp.
Entry (1C)
P
Timea Catalyst Conversionb
(bar) (h)
(mol%)
(%)
b : l b eeb
1c
2
30
30
30
35
35
50
60
60
50
65
2.5
2.5
10
3
14
3
16
11
16
4
15
3
0.4
0.4
0.4
0.25
0.25
0.05
0.4
0.4
0.025
0.01
62
99
98
>99
>99
>99
>99
>99
>99
>99
55
75
79
55
66
50
25
46
50
50
19
92
92
92
91
85
82
89
91
81
1
A H NMR spectrum of the reaction ‘mixture’ is archived in the
3
4d
5d
6e
7
ESI† and resembles a commercial sample (albeit contaminated
with traces of Rh that would need to be removed in downstream
reactions if used in a drug synthesis). While neat hydroformyla-
tions (and hydroformylation of mixtures of alkenes) are quite
widely reported,3a,7 the direct loading of a vessel with pre-catalyst,
ligand and as-received-substrate in air, followed by the conversion
2.5
0.5
8
10
10
12
1
5
6
9 f
10 f
a
The reaction times refer to either total reaction time, or if >99% to product of good purity seems of practical value. The best
complete, time after which >99% of gas was consumed. Pressure is
procedure we have discovered so far is shown in Table 1,
entry 9, although we also note that an unoptimised neat reaction
constant, a ligand : Rh ratio of 1.25 was used and [styrene] = 0.3 M in
b
toluene except where noted. Conversion and b:l determined by 1H NMR
(alkyl protons either against cyclooctane internal standard or alkene also worked using 0.01 mol% catalyst at 65 1C (T. O. F. =
2500 mol molÀ1
productivity we have observed is in the range suitable for
application in commercial processes.
h
À1), but gave lower ee. In any case, the
protons), and confirmed by GC. The ee was measured using capillary
GC (see ESI), and in all cases the S enantiomer was the major isomer.
c
d
Mismatched (R,S,S)-BOBPHOS used as chiral ligand. Ligand : Rh ratio
e
f
of 2.5 : 1, 0.63 M. 4 M concentration. No solvent, L : Rh = 2.5.
1476 | Chem. Commun., 2014, 50, 1475--1477
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Table 2 Enantioselective hydroformylation of vinyl arenes catalysed by
Rh/(S,S,S)-BOBPHOS
We thank Dr Reddys Laboratories (UK), the EPSRC-Chemistry
Innovation Network, and the Royal Society for funding.
Notes and references
‡ We also note here that when we have used a significant excess of
ligand (e.g. L : Rh of 2.5 : 1), rather than observe inhibition, the reaction
proceeded slightly faster than using the complex formed from [Rh(acac)-
(CO)2] and BOBPHOS without large excess of ligand. Whether excess
ligand prevents catalyst decomposition needs to investigated in our
future mechanistic studies. We certainly recommend an excess of ligand
for the no-solvent + no activation process.
1 (a) P. W. N. M. Van Leeuwen and C. Claver, Rhodium Catalysed
Hydroformylation, Kluwer Academic Publishers, Dordrecht, 2000;
Temp. Timea Catalyst Conversionb
´
(b) F. Ungvary, Coord. Chem. Rev., 2004, 248, 867; (c) M. Dieguez,
Entry Substrate (1C)
(h)
(mol%) (%)
b : l b eeb
`
O. Pamies and C. Claver, Tetrahedron: Asymmetry, 2004, 15, 2113;
(d) B. Breit and W. Seiche, Synthesis, 2001, 1; (e) R. Franke, D. Selent
1c
2
2a
2a
3a
4a
5a
5a
30
30
30
45
30
60
3
0.5c
0.5
0.5
0.05
0.5
0.4
>99
>99
>99 [89]
>99 [89]
>99 [96]
52 [46]
>80 89
>80 89
>80 89
54 90
75 86
48 89
¨
and A. Borner, Chem. Rev., 2012, 112, 5675.
3.5
4.5
9
6
1
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4c,d
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´
´
a
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The reaction times refer to either total reaction time, or if >99%
complete, time after which >99% of gas was consumed. Constant pressure
of 4 bar used, and a ligand : Rh ratio of 1.25 was used and [styrene] = 0.5 M
in toluene except where noted. b Conversion and b:l determined by
1H NMR (alkyl protons either against cyclooctane internal standard or
alkene protons), and confirmed by GC. >80 : 1 refers to either undetectable
linear aldehyde or measured values of c. 99% branched aldehyde content.
[Unoptimised yields of aldehydes of high purity (spectra in ESI).] The ee was
c
measured using capillary GC or HPLC (see ESI). Ligand : Rh ratio of 2.5 : 1.
´
`
´
d
e
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While many papers only report studies on styrene as a model
substrate, some of the more synthetically useful publications
also report other vinyl arenes. These can give less desirable
results in some cases; in the case of asymmetric hydroformyl-
ation of 4-chlorostyrene and 4-methoxystyrene, the class-leading
Landis ligands report a desired isomer yield down to 86.9% and
81% due to a drop-off in ee. We studied alkenes 2a and 3a under
the unoptimised low temperature conditions. The results
obtained for the 3- and 4-chloro styrenes (desired isomer yield
B94–95%) appear to be the best observed for these substrates.
Reactions were complete in several hours. To investigate if
more electron donating vinyl arenes could be used, we also
studied the hydroformylation of 4-vinyl anisole under solvent-
free conditions and got excellent results with a desired isomer
yield of 93.3%. 2-Methoxy-6-vinyl-naphthalene also gave good
results, although not quite matching the very best2f reported
(Table 2, entries 5 and 6).
´
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In summary, the use of rhodium complexes of (S,S,S)- 4 (a) G. M. Noonan, J. A. Fuentes, C. J. Cobley and M. L. Clarke, Angew.
Chem., Int. Ed., 2012, 51, 2477; (b) A couple of entries from Table 1
BOBPHOS as catalyst for the enantioselective hydroformylation
of vinyl arenes enables very high desired isomer yields with
were archived in
a patent: G. M. Noonan, C. J. Cobley and
M. L. Clarke, WO201201657A3, 2012.
good activity. The ability to give good activity at low pressures, 5 (a) V. F. Slagt, P. C. J. Kamer, P. W. N. M. van Leeuwen and J. N. H. Reek,
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2005, 9, 701.
the high solubility, and the ease of operation enable a solvent-
free highly enantioselective hydroformylation at low catalyst
loading directly delivering product of excellent purity. Projects 6 T. M. Konrad, J. Durrani, C. J. Cobley and M. L. Clarke, Chem.
Commun., 2013, 49, 3306.
7 (a) M. L. Clarke and G. J. Roff, Chem.–Eur. J., 2006, 12, 7978; (b) F. Shibahara,
K. Nozaki and T. Hiyama, J. Am. Chem. Soc., 2003, 125, 8555;
studying the mechanism of action of this unusually selective
catalyst, new related ligand systems and further applications
´
are getting underway.
(c) L. Monnereua, D. Semeril and D. Matt, Eur. J. Org. Chem., 2010, 3068.
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