The use of ligand 6, which differs from ligand 5 in that it has a
methyl substituent at C-5, showed practically no isomerization
combined with excellent regioselectivity and unprecedentedly high
ee’s (entry 6).
Table 1 Rh-catalyzed asymmetric hydroformylation of 1 using
diphosphite ligands 5–9a
Ligands 7–9 showed lower regio- and enantioselectivities than
ligands 5 and 6. This can be attributed to the higher isomerization
when this family of ligands is used than when the furanoside
ligands 5 and 6 are used. The results also indicated that the bridge
length affects the catalytic performance. Therefore, ligand 8,
which, like ligands 5 and 6, has three carbon atoms in the bridge,
provides higher regio- and enantioselectivites than ligands 7 and 9,
which have two and four carbon atoms in the bridge, respectively.
To sum up, these results indicate that the furanoside backbone
is more effective in transferring the chirality to the tetrahydro-
furan-3-carbaldehyde 2. In particular, note the excellent positive
effect of the presence of the methyl substituent at the C-5 position
of the furanoside backbone (ligand 6) in inhibiting the isomeriza-
tion process and transferring the chiral information. Ligand 6
therefore competes favourably with the binaphos ligand, which so
far has provided the best enantioselectivities for this substrate
(entry 6 vs. 10).
Entry Ligand
% Convb % Ald. (2/4)c % 3d % ee of 2e
1
5
5
5
5
5
6
7
8
9
100
100
100
100
100
100
100
100
100
88 (100/0)
82 (89/11)
75 (100/0)
98 (95/5)
87 (100/0)
99 (99/1)
100 (72/28)
99 (95/5)
100 (64/36)
100 (100/0)
12
18
25
2
13
1
0
1
0
0
53 (S)
31 (S)
53 (S)
37 (S)
53 (S)
74 (S)
,5
23 (R)
,5
64 (R)
2f
3g
4h
5i
6
7
8
9
10j
a
binaphos 100
P 5 18 bar, pCO/pH2 5 1, [Rh(acac)(CO)2] (0.012 mmol), 1/Rh 5
b
400, toluene (5 mL), Ligand/Rh 5 2, T 5 45 uC, t 5 24 h. Total
conversion measured by 1H NMR. Conversion into aldehydes
c
determined by 1H NMR. Isomerization measured by 1H NMR.
d
e
Enantioselectivity of 2 measured by 1H NMR using Eu(hfc)3.
Ligand/Rh 5 1. Ligand/Rh 5 4. t 5 48 h. pCO/pH2 5 2. P 5
f
g
h
i
j
20 bar, [Rh(acac)(CO)2] (0.012 mmol), 1/Rh
(1.5 mL), Ligand/Rh 5 4, T 5 40 uC, t 5 24 h.
5 400, benzene
Diphosphite ligands 5–9 were also tested in the Rh-catalyzed
asymmetric hydroformylation of 2,3-dihydrofuran 3. The results
are summarized in Table 2. The catalysts were prepared as for the
hydroformylation of 1.{ In no cases were isomerized (product 1),
hydrogenated or polymerized products of 2,3-dihydrofuran
observed. The results followed the same trend as for the
hydroformylation of 1. The furanoside diphosphites were superior
in terms of regio- and enantioselectivities to the pentanediol-based
diphosphite and the binaphos ligands (entries 1 and 2 vs. entries 3
and 4). Again ligand 6, with a methyl substituent at C-5 position,
provided unprecedented enantioselectivities in favour of the
tetrahydrofuran-3-carbaldehyde 2 (entry 2). Note, however, that
the sense of enantioselectivity was opposite to that of the
hydroformylation of 2,5-dihydrofuran 1 (entry 2, Table 2 vs. entry
6, Table 1). Using the same ligand 6, this important feature enables
the synthesis of both enantiomers of tetrahydrofuran-3-carbalde-
hyde 2 by simple substrate change.
Table 2 Selected results for the Rh-catalyzed asymmetric hydrofor-
mylation of 3 using diphosphite ligandsa
Entry
Ligand
% Convb
% Ald. (2/4)c
% ee of 2d
1
2
3
4e
a
5
6
88
88 (78/22)
100 (76/24)
100 (68/32)
100 (50/50)
48 (R)
75 (R)
43 (S)
38 (S)
100
100
100
8
binaphos
P 5 18 bar, pCO/pH2 5 1, [Rh(acac)(CO)2] (0.012 mmol), 3/Rh 5
b
400, toluene (5 mL), Ligand/Rh 5 2, T 5 45 uC, t 5 48 h. Total
conversion measured by 1H NMR. Conversion into aldehydes
c
In conclusion, we have shown that diphosphite ligands are
suitable for the Rh-catalyzed hydroformylation of 2,5- and 2,3-
dihydrofurans. We have found that the degree of isomerization
and the effectiveness in transferring the chiral information in the
product can be tuned by an appropriate choice of ligand.
Unprecedentedly high enantioselectivities for both substrates have
therefore been obtained using the furanoside diphosphite ligand 6.
Note that both enantiomers of tetrahydrofuran-3-carbaldehyde 2
can be synthesized using the same ligand 6 by simple substrate
change. These results open up the hydroformylation of hetero-
cyclic compounds to the potential effective use of readily available
and highly modular diphosphite ligands.
determined by 1H NMR. Enantioselectivity of 2 measured by 1H
NMR using Eu(hfc)3. P 5 20 bar, [Rh(acac)(CO)2] (0.012 mmol),
d
e
3/Rh 5 400, benzene (1.5 mL), Ligand/Rh 5 4, T 5 40 uC, t 5 24 h.
absolute configuration of the predominant enantiomer of 2
obtained from 3 is R, which is opposite to that from 1. These
results show that the absence of isomerization of the substrate is
important for achieving high enantioselectivity from the reaction
of 1. Indeed, the ee of 2 dropped when the hydroformylation of 3,
which is formed from the isomerization of 1, took place at a low
ligand-to-rhodium ratio (entry 2).
This work was supported by the Spanish Ministerio de
Educacio´n, Cultura y Deporte (BQU2001-0656), the Spanish
Ministerio de Ciencia y Tecnologia (Ramon y Cajal fellowship to
O.P.) and the Generalitat de Catalunya (Distinction to M.D. and
C.C.)
It is generally accepted that isomerization occurs as a result of
competition between the b-hydride elimination process and CO
insertion (Scheme 1). Therefore, as a high CO pressure is necessary
to suppress isomerization, we then performed an experiment by
increasing the CO partial pressure. However, the rate of
hydroformylation vs. isomerization was unaffected (entry 5 vs. 1).
The rest of ligands were compared under standard conditions
(i.e. ligand-to-rhodium ratio of 2, 24 h reaction time and
pCO/pH2 5 1).
Montserrat Die´guez,* Oscar Pamies and Carmen Claver*
Departament de Qu´ımica F´ısica i Inorga`nica. Universitat Rovira i
Virgili. C/Marcel?li Domingo, s/n. 43007 Tarragona, Spain.
E-mail: montserrat.dieguez@urv.net
1222 | Chem. Commun., 2005, 1221–1223
This journal is ß The Royal Society of Chemistry 2005