Mazuela et al.
JOCArticle
SCHEME 1. Proposed Mechanism for the Isomerization Process
olefins, which provide access to important building blocks
for synthesizing natural products and pharmaceuticals.6
This is mainly because, for this kind of substrate, as well as
having to control the enantioselectivity of the process,
chemo- and regioselectivity are often a problem.6,7 For
example, in the hydroformylation of 2,5-dihydrofuran 1
the expected product is tetrahydrofuran-3-carbaldehyde 2
(Scheme 1). However, considerable amounts of 2,3-dihydro-
furan 3 and tetrahydrofuran-2-carbaldehyde 4 can also be
formed due to an isomerization process that takes place
simultaneously with the hydroformylation reaction. When
the 2,5-dihydrofuran 1 reacts with the rhodium hydride
complex, the 3-alkyl intermediate is formed. This can evolve
to 2,3-dihydrofuran 3 via the β-hydride elimination reaction.
Similarly, this new substrate can evolve to produce the
2-alkyl and 3-alkyl intermediates. Although the formation
of the 3-alkyl intermediate is thermodynamically favored,
the acylation occurs faster in the 2-alkyl intermediate.6b
Regioselectivity is therefore dominated by the rate at which
the acyl complex is formed.
For a considerable time, only the phosphine-phosphite
binaphos ligand provided good regio- and enantiocontrol in
the Rh-catalyzed asymmetric hydroformylation of hetero-
cyclic compounds.8 Several diphosphines,6c including some
diphospholanes and the bis-(diazaphospholodine) ESPHOS
ligand,9 have been applied but with little success (ee’s up to
32%). When diphosphites were used as ligands for the
Rh-catalyzed hydroformylation of vinylarenes, activities
and enantioselectivities were comparable to the best in the
literature, obtained using the binaphos ligand.2 However,
they have been used very little in the hydroformylation of
heterocyclic substrates. This is mainly because extensive
isomerization had been observed when phosphite ligands
are used.7
sugar derivatives L4 and L7, and kelliphite L17). We have
also evaluated systematic modifications of several ligand
parameters in these prominent ligands, which are known
to have an important effect on catalytic performance.
Therefore, with this library, we have investigated how
the ligand backbone, the length of the bridge, and the
substituents of the biphenyl moieties affected activities and
selectivities (chemo-, regio-, and enantioselectivity). By
carefully selecting these elements, we have achieved high
regio- and enantioselectivities and activities in different
substrates.
2. Results and Discussion
2.1. Asymmetric Hydroformylation of Five-Membered Het-
erocyclic Olefins. Diphosphite ligands L1-L17a-e were first
used in the Rh-catalyzed asymmetric hydroformylation of
2,5-dihydrofuran 1. The catalysts were prepared in situ by
adding the corresponding diphosphite ligand to [Rh(acac)-
(CO)2] as a catalyst precursor.
Initially, we determined the optimal reaction conditions
by conducting a series of experiments with ligand L10c in
which the ligand-to-rhodium ratio, CO/H2 pressure ratio,
temperature, reaction time, and substrate-to-rhodium ratio
were varied (Table 1).
In 2005, we reported the first successful application of a
diphosphite ligand in the Rh-catalyzed asymmetric hydro-
formylation of 2,5- and 2,3-dihydrofurans.10 Despite this
success, other diphosphite ligands have not yet been re-
ported, and the possibilities offered by diphosphites as new
ligands for this process still need to be studied. To fully
investigate these possibilities, in this paper we extend our
previous study (2005) to other diphosphite ligands (Figure 1)
and other types of heterocyclic olefins.
To do so, we have synthesized and screened a library of 64
potential diphosphite ligands.11 The ligands we have chosen
are representative of the most successfully applied families of
diphosphite ligands in hydroformylation (chiraphite L3,
Varying the ligand-to-rhodium ratio showed that the
combination of chemo-, regio-, and enantioselectivities was
best when 2 equiv of ligand was used (Table 1, entries 1-3). A
lower ligand-to-rhodium ratio decreased the regio- and
enantioselectivities in aldehyde 2 (Table 1, entry 1), while a
higher ligand-to-rhodium ratio negatively affected chemos-
electivity and increased the formation of isomerized product
3 (Table 1, entry 3).
It is generally accepted that isomerization occurs as a
result of competition between the β-hydride elimination
process and CO insertion (Scheme 1). Since a high CO pre-
ssure is needed to suppress isomerization, we conducted
experiments with increased CO partial pressure. This did
not affect the rate of hydroformylation vs isomerization
(Table 1, entries 2 vs 5), though decreasing the CO/H2
pressure ratio negatively affected chemoselectivity, which
increased the formation of isomerized product 3 (Table 1,
entries 2 vs 6).
A prolonged reaction time increased conversion into
aldehydes (Table 1, entry 4) but decreased regio- and enanti-
oselectivity in the desired product 2 (Table 1, entry 2 vs 4). To
study whether the hydroformylation of the formed isomer
2,3-dihydrofuran 3 accounts for this lost of selectivity, we
performed the hydroformylation of 3 under the same reac-
tion conditions. After 48 h, the hydroformylation of 3
afforded a 78:22 mixture of (R)-2 (48% ee) and 4 in 88%
conversion (Table 3, entry 11). By comparing these results,
we concluded that the loss of regioselectivity with the
(6) (a) Vietti, D. E. U.S. Patent 4376208, 1983.(b) Hoiuchi, T.; Ota, T.;
Shirakawa, E.; Nozaki, K.; Takaya, H. J. Org. Chem. 1997, 62, 4285. (c) del Rio,
I.; van Leeuwen, P. W. N. M.; Claver, C. Can. J. Chem. 2001, 79, 560.
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(7) (a) Polo, A.; Real, J.; Claver, C.; Castillon and, S.; Bayon, J. C.
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J. Chem. Soc., Chem. Commun. 1990, 600. (b) Polo, A.; Claver, C.; Castillon,
S.; Ruiz, A.; Bayon, J. C.; Real, J.; Mealli and, C.; Masi, D. Organometallics
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1992, 11, 3525.
(8) Several modifications of the Binaphos-type ligand have been studied.
See ref 6b.
(9) Unpublished results. For instance: (R,R)-Ph-BPE (22% ee), (R,R)-iPr-
BPE (18% ee), and ESPHOS (32% ee).
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(10) Dieguez, M.; Pamies, O.; Claver, C. Chem. Commun. 2005, 1221.
(11) These ligands have the advantages of phosphite ligands: they are
obtainable at a low price from readily available alcohols, are highly resistant
to oxidation, and have facile modular constructions. See, for instance: (a)
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Reference 2e. (b) Dieguez, M.; Pamies, O.; Ruiz, A.; Claver, C. In Methodol-
ogies in Asymmetric Catalysis; American Chemical Society: Washington, DC,
2004; Chapter 11.
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