An asymmetric hydroformylation catalyst that delivers branched aldehydes from alkyl alkenes

Article abstract of DOI:10.1002/anie.201108203

Surprising selectivity: The first enantioselective hydroformylations of simple alkenes of type RCH₂CH=CH₂ to preferentially deliver the branched aldehyde product have been discovered using a new chiral ligand, named bobphos (see scheme). Established ligands are unselective in this reaction or show a slight preference towards the linear aldehyde. Copyright

Full text of DOI:10.1002/anie.201108203

Angewandte
Chemie
DOI: 10.1002/anie.201108203
Hydroformylation
An Asymmetric Hydroformylation Catalyst that Delivers Branched
Aldehydes from Alkyl Alkenes**
Gary M. Noonan, Josꢀ A. Fuentes, Christopher J. Cobley,* and Matthew L. Clarke*
Enantioselective hydroformylation of alkenes can simulta-
of any real leads have confined these efforts to screening
novel catalysts that were originally designed to solve other
problems in carbonylation catalysis. In one recent research
project aimed at further tuning the excellent performance of
the important asymmetric hydroformylation ligands, Kelli-
phite and Ph-bpe, we considered a hybrid non-symmetric
ligand that would present the best of both these ligands, and
might gain advantage from being non-C2 symmetric. Phos-
phine-phosphites have attracted much interest in hydro-
formylation,[2g,l–q] although phospholano derivatives or deriv-
À
neously create a new C C bond, install a very versatile
functional group, and produces enantiomerically enriched
compounds from very economic reagents: an alkene, carbon
monoxide, and hydrogen. Given the precedent for large-scale
production of achiral linear aldehydes, hydroformylation can
be viewed as potentially the ideal reaction for commercial
production of chiral building blocks.[1] However, there have
been far more hurdles to overcome relative to core asym-
metric production methods such as asymmetric hydrogena-
tion, despite decades of research effort.
atives using a CH2O backbone are not well studied.[2n,p] The
ligand, that we have tended to refer to as bobphos (“best of
both phosphorus ligands”), (Sax,S,S)-4, can be produced
reliably by the route shown in Scheme 1 from the known
precursor 1.[5] The phosphite coupling was accomplished by
activating (S)-2 with Me3SiI; this does not proceed cleanly
and the ca. 40:60 mixture of iodide (S)-3 and (S)-2 was reacted
directly with the known precursor 1 in the presence of
DABCO as base and deprotecting agent to give, after
purification, (Sax,S,S)-4.[5] (Rax,S,S)-4 was also prepared from
(R)-2.
À
À
After intensive research effort, a range of catalysts that
give good enantiomeric excess (ee) for model substrates (e.g.
styrene) are now available.[2] There is now substantial
research and commercial interest in making products of
relevance to the pharmaceutical industry and organic syn-
thesis using this technology.[3] Despite all this activity, the
control of regioselectivity towards the branched aldehyde is at
best only a partially resolved issue. Certain well-known
substrates like styrene give the branched aldehyde with
a typical regioselectivity of around 10:1, which is usable after
purification, although higher selectivity is desirable. Some
functionalized substrates show a very high preference for the
branched aldehyde with the correct choice of catalyst, and
ligands that simultaneously act as reversible auxiliaries for the
substrate and bind rhodium have been applied successfully to
control regioselectivity for specific functionalized alkenes.[4]
A completely unresolved issue that would represent a huge
step forward is the controlled formation of branched chiral
aldehydes from simple terminal alkyl olefins of type
This ligand was initially examined in the hydroformylation
of the model substrate, vinyl acetate (Scheme 2). Bobphos
delivered > 99% conversion to aldehyde after 4 h at 2.5 bar
pressure at 608C; the linear isomer was observable only in
trace quantities (see Supporting Information) and an 83% ee
was measured. The other diastereomer of the ligand,
(Rax,S,S)-4 made from the opposite enantiomer of chiral
diol, gave 32% ee of the opposite enantiomer of 2-acetox-
ypropanal (not shown); a classic matched/mismatched sce-
nario for a multiple-stereocenter ligand.
=
RCH2CH CH2. Here we show the most significant progress
yet towards this general goal, with the first catalytic reactions
that combine significant regioselectivity and enantioselectiv-
With this encouraging result in hand, we considered the
use of bobphos in hydroformylations of alkenes of type
=
=
ity for alkenes of type RCH2CH CH2.
RCH2CH CH2. Due to high demand in the commodity
We have had a long-standing interest in obtaining
branched aldehydes from alkyl alkenes, but in the absence
chemicals industry for linear alkyl aldehydes, an extremely
large set of ligands has been tested in the hydroformylation of
substrates such as hex-1-ene. Almost without exception, the
linear aldehyde is produced preferentially, with some ligands
delivering exquisite linear selectivity.[1] A couple of examples
where branched aldehydes are formed in preference to linear
product are not enantioselective.[6] An example where a chiral
ligand was examined in this class of alkenes was an interesting
study by Nozaki and co-workers using the important binaphos
ligand; enantioselective hydroformylation of hex-1-ene gave
good enantioselectivity, but the undesired linear aldehyde was
more than 75% of the product mix (b:l = 1:3.0).[7] It was
therefore with meagre expectations that we tested bobphos in
[*] Dr. G. M. Noonan, Dr. J. A. Fuentes, Dr. M. L. Clarke
School of Chemistry, University of St Andrews, EaStCHEM
St Andrews, Fife, KY16 9ST (UK)
E-mail: mc28@st-andrews.ac.uk
Dr. C. J. Cobley
Chirotech Technology Ltd., Dr. Reddy’s Laboratories (EU) Limited
410 Cambridge Science Park, Milton Road
Cambridge, CB4 OPE (UK)
E-mail: ccobley@drreddys.com
[**] The authors thank the EPSRC and Dr. Reddy’s Laboratories for
funding, and EPSRC for the use of the National Mass Spectrometry
Service.
a
selection of hydroformylations of alkenes of type
=
RCH2CH CH2 (Scheme 3 and Tables 1 and 2).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108203.
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Table 1: Hydroformylation of allyl benzene (10a) using a range of
hydroformylation catalysts at room temperature.
Entry[a]
Ligand
Product
b:l[b]
ee[c]
yield [%][b]
1
2
3
4
5
6
7
8
9
10
Ph3P
5
46
86
91
93
56
52
66
1:1.1
1:1.2
1:1.1
1:1.8
1:1.0
1:1.2
1:1.1
1:1.0
4.0:1
3.6:1
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
0
5
90
88
6
7
dppe[d]
dppf[d]
8
9
4
4
87
64[e]
39[f]
[a] 0.4 mol% [Rh(acac)(CO)2] and 0.5 mol% bidentate ligand or
1.2 mol% monodentate ligand were stirred at 5 bar syngas at 508C for
40 min in toluene (2 mL), prior to running reactions at 168C at 5 bar
initial syngas pressure for 3 days. [b] % Product determined by 1H NMR
spectroscopy using Et4Si as internal standard. [c] Determined by HPLC
analysis of the alcohol formed after reduction with NaBH4.
[d] dppe=1,2-bis(diphenylphosphino)ethane; dppf=1,1’-bis(diphenyl-
phosphino)ferrocene. [e] 53% yield of the corresponding alcohol over
two steps after purification. [f] Reaction time of 4 h at 308C.
favors the formation of the branched aldehyde. All catalysts
were pre-formed under a syngas atmosphere at 508C since
this is advisable if hydroformylations are to be attempted
under such mild conditions. All the established ligands are
unselective or show a slight preference towards the linear
aldehyde. In contrast, bobphos gives 80% selectivity in favor
of the branched aldehyde (Table 1, entry 9: only 2-methyl-3-
phenylpropanal and linear 4-phenylbutanal were detected).
Moreover, control of enantioselectivity is also possible with
90% ee in favor of the (S) enantiomer observed at room
temperature. Another surprising result is that Kelliphite and
Ph-bpe, the ligands from which bobphos is derived from, give
no enantioselectivity in these reactions; a result we have triple
checked and have no explanation for, although we note that
most hybrid ligands made from two very successful ligands
perform worse than the parent ligands, while in this case the
hybrid is of two ligands that are very poor for this substrate!
We have tested a range of other substrates that should be
linear selective; in order to prepare racemic standards for
analytical development, all of these substrates were examined
using ligand 6, previously one of the few ligands to favor
branched aldehyde formation to some degree and this
generally gave moderate selectivity towards the linear
aldehyde (see Supporting Information). By using the new
(Sax,S,S)-bobphos catalyst system, we have observed prefer-
ential formation of the branched aldehyde for the first time,
and with high enantioselectivity for the (S) isomer.
Scheme 1. Synthesis of “bobphos” and numbering scheme for other
ligands used in this study. DABCO=1,4-diazabicyclo[2.2.2]octane.
Scheme 2. Enantioselective hydroformylation of vinyl acetate can be
accomplished by using Rh/bobphos catalyst.
The results are, to say the least, rather surprising. Table 1
shows hydroformylation of allyl benzene (10a) using a variety
of phosphine ligands known to be proficient in hydroformy-
lation. Unusually, these studies were carried out at temper-
atures as low as 158C, since our studies have shown that this
In the reactions in Table 2, we have generally used quite
long reaction times and unusually low temperatures to
maximize ee, but as shown (Table 2, entries 2 and 3), a slight
increase in temperature enables the conversion of 10b into
products in a few hours with very similar results. In addition to
opening up the prospect of a general, practical branched-
selective hydroformylation methodology in the future, the
ready availability of simple alkenes means that, depending on
the ability to purify products downstream, this catalyst may
Scheme 3. Enantioselective hydroformylation of alkenes of type
=
RCH2CH CH2.
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Angewandte
Chemie
=
Table 2: Hydroformylation of alkenes of type RCH2CH CH2 using Rh/
bobphos catalyst, (Sax,S,S)-4.
the way towards a significant expansion in the scope of Rh-
catalyzed hydroformylation processes.
Entry[a] Substrate T [8C] Conv. Product
t [h] b:l[b]
ee[c]
[%][b] yield [%][b,d]
Received: November 22, 2011
Published online: January 27, 2012
1
2
3
4
5
6
7
8
9
10b
10b
10b
10c
10d
10e
10 f[e]
10 f[e]
10g
16
30
40
16
16
16
30
60
16
81
75
90
99
89
81
75
90
99
89
21
8
4
66
70
46
14
0.6
29
6.2:1
5.4:1
5.3:1
3.0:1
2.5:1
3.0:1
10.0:1 81
8.7:1
4.5:1
91
89
88
92
75
93
Keywords: alkenes · asymmetric hydroformylation ·
.
carbonylation · phosphine-phosphite ligands · regioselectivity
78
70
>99
>99
72
>99
>99
71
71
92
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5 bar syngas at 508C in toluene, prior to running reactions at 5 bar initial
syngas pressure at temperature and time specified. [b] % Conver-
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already be practical. For example, aldehydes of general
formula ArCHCH(CHO)Me are of importance to the
fragrance industry, with lillial being one of the most important
of these at present. Lillial is the product formed from
branched-selective hydroformylation of simple alkene 10c.
This is considerably more direct than alternative asymmetric
syntheses.[8] Whether a single enantiomer is required or not,
the alternative procedure reported here delivers significant
conversion to lillial in a very direct manner.
There are also commercial products that could be
produced from (S)-methyl hexanal that require several
steps, a procedure starting from very cheap hex-1-ene is
potentially very attractive.[9] Using Rh/bobphos gave the
branched aldehyde as the major product and with high
enantioselectivity (93% ee).
Allyl cyanide is a substrate that, while fitting our
=
RCH2CH CH2 classification, would be expected to deliver
the branched isomer with modest regioselectivity;[2c,j] the
results obtained with bobphos are amongst the best observed.
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our knowledge, been examined before and was hydroformy-
lated with good selectivity to the branched isomer, in contrast
to a reaction using a Rh catalyst and ligand 6 that was
modestly linear selective (Table 2, entry 9, and see Supporting
Information, Table S1). In all the reactions conducted with
Rh/bobphos, we have never detected any isomerized alkenes
or other branched aldehydes that may result from hydro-
formylation of the internal alkenes. Given that the catalyst
also performs best under conditions that would hinder
isomerization, this ligand exerts a strong preference towards
branched aldehyde formation from the terminal alkene.
In conclusion, a new phosphine-phosphite ligand has been
found to give the branched aldehyde with significant selec-
tivity even in the hydroformylation of alkyl olefins of type
=
RCH2CH CH2. In addition, it produced these chiral alde-
hydes with high enantioselectivity. This discovery should open
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