Highly efficient rhodium catalysts for the asymmetric hydroformylation of vinyl and allyl ethers using C1-symmetrical diphosphite ligands

Article abstract of DOI:10.1002/adsc.200900608

Here, we describe the successful application of novel glucofuranose-derived 1,3-diphosphites in the rhodium-catalysed asymmetric hydroformylation of vinyl acetate, 2,5-dihydrofuran and 2,3-dihydrofuran. In the hydroformylation of vinyl acetate, total regioselectivity and high ee (up to 73%) were obtained. When 2,3- and 2,5-dihydrofuran were the substrates, total chemo- and regioselectivities were achieved together with ees up to 88%. These results correspond to the highest ee values reported to date in the asymmetric hydroformylation of these substrates. The HP-NMR studies of the [RhH(CO) ₂(L)] species (L=15 and 17) demonstrated that both ligands coordinate to the Rh centre in an eq-eq fashion. The complex [RhH(CO)₂(15)] was detected as a single isomer with characteristic features of eq-eq coordination. However, the broadening of the corresponding signals indicated that this species is rapidly interchanging in solution. In contrast, complex [RhH(CO) ₂(17)] was detected as a mixture of two conformational isomers at low temperature due to the greater flexibility of the monocyclic backbone of this ligand.

Full text of DOI:10.1002/adsc.200900608

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DOI: 10.1002/adsc.200900608
Highly Efficient Rhodium Catalysts for the Asymmetric
Hydroformylation of Vinyl and Allyl Ethers using
C1-Symmetrical Diphosphite Ligands
Aitor Gual,a Cyril Godard,a Sergio Castillꢀn,b,* and Carmen Clavera,*
a
Departament de Quꢁmica Fꢁsica I Inorgꢂnica, Universitat Rovira I Virigli, Marcel·li Domingo, s/n, 43007 Tarragona, Spain
Fax : (+34)-977-559-563; e-mail: carmen.claver@urv.cat
Departament de Quꢁmica Analꢁtica I Orgꢂnica, Universitat Rovira I Virigli, Marcel·li Domingo, s/n, 43007 Tarragona,
b
Spain
Fax : (+34)-977-558-446; e-mail: sergio.castillon@urv.cat
Received: September 3, 2009; Revised: December 3, 2009; Published online: February 11, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900608.
Abstract: Here, we describe the successful applica- gands coordinate to the Rh centre in an eq-eq fash-
tion of novel glucofuranose-derived 1,3-diphosphites ion. The complex [RhH(CO)2(15)] was detected as a
in the rhodium-catalysed asymmetric hydroformyla- single isomer with characteristic features of eq-eq co-
tion of vinyl acetate, 2,5-dihydrofuran and 2,3-dihy- ordination. However, the broadening of the corre-
drofuran. In the hydroformylation of vinyl acetate, sponding signals indicated that this species is rapidly
total regioselectivity and high ee (up to 73%) were interchanging in solution. In contrast, complex
obtained. When 2,3- and 2,5-dihydrofuran were the [RhH(CO)2(17)] was detected as a mixture of two
substrates, total chemo- and regioselectivities were conformational isomers at low temperature due to
achieved together with ees up to 88%. These results the greater flexibility of the monocyclic backbone of
correspond to the highest ee values reported to date this ligand.
in the asymmetric hydroformylation of these sub-
strates. The HP-NMR studies of the [RhH(CO)2(L)] Keywords: carbohydrates; dihydrofurans; diphos-
species (L=15 and 17) demonstrated that both li- phites; enantioselectivity; hydroformylation
Introduction
tecting groups. These groups can also be used to vary
the size of the chelate with the metal and to tune the
The synthesis of enantioenriched aldehydes is an im- behaviour of the ligand in terms of catalytic proper-
portant target in organic chemistry due to versatility ties. The main drawbacks of carbohydrate-based li-
of the aldehyde function. For this purpose, asymmet- gands are: a) only one enantiomer is available. This
ric hydroformylation is a challenging transition metal- can be partially overcome by changing the relative
catalysed process that is of special interest.[1–4] Rhodi- configuration of the various stereogenic centres in the
um catalysts modified with phosphorus ligands are molecule, and b) some of the ligands often require
the most successful catalytic systems in the asymmet- long synthetic sequences.
ric hydroformylation reaction,[5] and phosphites are
CHIRAPHITE ligand 1 provided high ees (up to
among the ligands that provided the best results.[6–12] 90%) in the rhodium-catalysed hydroformylation of
Phosphites are very versatile ligands due to the vinylarenes, which is the benchmark reaction in this
straightforwardness of their synthesis from chiral diols field.[6,7] In contrast, KELLIPHITE ligand 2 provided
and the ease of modifying the bisphenol moiety. In low enantioselectivities.[12] Diphosphite 3, which con-
this context, carbohydrates are suitable starting mate- tains a glucofuranose backbone, provided similar ees
rials because the presence of several hydroxy groups to those obtained with 1. Diphosphite 4 afforded an
offers several possibilities to introduce phosphorus enantioselectivity close to that of 3 but produced the
functions.[13] Moreover, the availability of various pro- opposite enantiomer, showing that one of the limita-
tecting procedures makes possible the synthesis of tions of the carbohydrate ligands could be circumven-
many different structures by simply varying the pro- ted.[11c,d] BINAPHOS 5 and YANPHOS 6 are the
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Aitor Gual et al.
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most relevant members of the phosphine-phosphite
ligand family and provide excellent enantioselectivi-
ties in the hydroformylation of styrene.[14,15]
However, the hydroformylation of vinyl and allyl
ethers such as dihydrofuran derivatives and vinyl ace-
tate proved to be much more challenging and has
been much less studied. In the asymmetric hydrofor-
mylation of vinyl acetates, the most successful results
in terms of regioselectivity and enantioselectivity
were described using BINAPHOS 5[14] and the phos-
phine-aminophosphite
(Scheme 1).
ligand
YANPHOS
6[15]
The Rh/diphosphite KELLIPHITE ligand 2 catalyt-
ic system was found to be efficient in this reaction
yielding excellent regioselectivity (99%) with 88% ee
(Scheme 2).[12] In contrast, the CHIRAPHITE ligand
1 provided only moderate enantioselectivity in this re-
action.[5a] Recently, high regioselectivities and enan-
tioselectivites were reported using bis-phospholane li-
Scheme 2. Rhodium-catalysed hydroformylation of vinyl
acetate, 2,5- and 2,3-dihydrofurans using phosphorus ligands.
gands, such as Binapine,[16] TangPhos,[16] Ph-Bpe,[17]
Esphos,[18] as well as bis-3,4-diazaphospholane[19] and
bis-phosphonite ligands.[20]
The first successful report concerning the synthesis
of tetrahydrofuran-3-carbaldehyde 12 by Rh-catalysed
asymmetric hydroformylation of 2,3- and 2,5-dihydro-
furans was published by Nozaki in 1997
(Scheme 2).[21] The catalytic system bearing the
BINAACTHNUTRGNEPUNG HOS ligand 5 afforded moderate to high
enantioselectivities (ee up to 64%) in the hydroformy-
lation of 2,5-dihydrofuran 10 and low to moderate
enantioselectivities when 2,3-dihydrofuran 11 (ee up
to 38%) was the substrate. The highest enantioselec-
tivities in the asymmetric Rh-catalysed hydroformyla-
tion of 2,5-dihydrofuran 10 and 2,3-dihydrofuran 11
(ee up to 74% S and R, respectively) were reported
using the 1,3-diphosphite 3 (Scheme 2).[22]
The simultaneous control of the chemo-, regio- and
enantioselectivities in the Rh-catalysed asymmetric
hydroformylation of dihydrofurans is a key issue. Our
group previously reported that when 2,5-dihydrofuran
10 is the substrate, high degrees of isomerisation into
the corresponding vinyl ether 11 are observed.[23,24]
This competing isomerisation process has a great
impact on the enantioselectivity of the hydroformyla-
tion reaction since each isomer yields the opposite
enantiomer of the same aldehyde. Thus, a high degree
of isomerisation results in low ee values.[21,22,24]
The proposed mechanism for the Rh-catalysed hy-
droformylation of 2,5-dihydrofuran 11 and 2,3-dihy-
drofuran 12 is presented in Scheme 3.[21–24] First, the
alkene coordinates to rhodium hydride species, and
the 2- or 3-alkyl complexes are formed by subsequent
migratory insertion. Carbonylation of these species
yields acyl complexes which react with H2 to reduc-
tively eliminate the aldehyde product(s) and regener-
ate the initial hydride species. The previously men-
tioned isomerisation between allyl and vinyl ethers is
Scheme 1. Rhodium-catalysed asymmetric hydroformylation
of styrene using phosphorus ligands 1–6.
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Highly Efficient Rhodium Catalysts for the Asymmetric Hydroformylation
Scheme 3. Mechanism of the rhodium-catalysed asymmetric hydroformylation of 2,5-dihydrofuran 10 and 2,3-dihydrofuran
11.
AHCTUNGTREGdNNUN eneglucofuranose (18). Ligand 3 (for comparative
purposes) and ligands 14 and 17 were prepared from
the diols 20, 23 and 26, respectively. The syntheses of
these diols were previously reported by our group
(Scheme 4).[25]
To synthesise the diol 22, precursor of ligand 14,
the starting compound 18 was treated with N-
bromosucACHTUNRGTNEcUGN inimide (NBS)/PPh3 to obtain the corre-
sponding 6-bromo derivative, which was isolated in
78% yield (Scheme 4).[25,26] This reaction involves the
migration of the 5,6-O-isopropylidene group to a 3,5-
O-isopropylidene with concomitant entry of bromide
at the C-6 position.[27] Subsequent treatment with
sodium nitrite gave alcohol 21. Alkylation of the alco-
hol with BuBr and selective deprotection of the 3,5-
O-isopropylidene group afforded 22 in 23% overall
yield.
Figure 1. Chiral diphosphite ligands 14–17 used in this study.
The diol 25, precursor of ligand 16, was synthesised
governed by the equilibrium between the two rhodi- in a straightforward manner in two steps (Scheme 4).
um hydride alkene species (Scheme 3) that occurs First, the selective opening of the 5,6-O-isopropyli-
through insertion/b-H-elimination. It is noteworthy dene group of 18 was achieved by reaction with
that the formation of the 3-alkyl intermediate was BF3·Et2O and using trimethylallylsilane as nucleophile
shown to be thermodynamically favoured,[23] although source.[28] This step was followed by the reduction of
the carbonylation of the 2-alkyl species was shown to the double bond by hydrogenolysis using Pd/C as cat-
be faster than that of the 3-alkyl species.[23]
Here we report the systematic modification of 40%.
alyst. The overall yield for the synthesis of diol 25 was
ligand 3 which consists in increasing the bulkiness at
Finally, the diols 20, 22, 23, 25 and 26 were treated
position C-6 (ligands 14–16, Figure 1) and removing with phosphorochloridites derived from 3,3’-5,5’-tetra-
the 1,2-O-isopropilydene group (ligand 17, Figure 1). tert-butyl-1,1’-bisphenol (Scheme 5), that were previ-
These new ligands yielded excellent results in the rho- ously synthesised in situ by standard procedures to
dium-catalysed hydroformylation of 2,3- and 2,5-dihy- yield the corresponding diphosphite ligands 3, 14, 15,
drofurans.
16 and 17 in moderate to good yields (50–75%).[29]
All these ligands were characterised by multinuclear
NMR spectroscopy and elemental analysis (See Ex-
perimental Section for spectroscopic details).
Results and Discussion
Synthesis of Diphosphite Ligands with a
Carbohydrate Backbone
Rh-Catalysed Asymmetric Hydroformylation
The ligands 14–17 (Figure 1) were synthesised from Catalytic systems containing the chiral diphosphites
the commercially available 1,2:5,6-O-di-isopropyli- previously synthesised were used in the rhodium-cata-
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Scheme 5. Synthesis of chiral diphosphite ligands (3, 14–17)
used in this study.
(ratio 1:1) and heated at the desired temperature. The
results are summarised in Table 1, Table 2, and
Table 3.
In Table 1, the results obtained for the rhodium-cat-
alysed hydroformylation of vinyl acetate 8 in 24 h
under standard conditions using the 1,3-diphosphites
Table 1. Rhodium-catalysed asymmetric hydroformylation of
vinyl acetate (8) using diphosphites 3, 14–17.
Entry[a]
Ligand
Conv. [%][b] Regio. [%][c]
ee [%][d]
1
3
3
3
14
15
15
15
16
17
100
47
43
100
100
20
18
100
100
99
65 (R)
70 (R)
73 (R)
41 (R)
60 (R)
66 (R)
68 (R)
48 (R)
51 (R)
2[e]
3[e,f]
4
>99
>99
99
5
99
Scheme 4. Synthesis of diols 20, 22, 23, 25 and 26.
6[e]
7[e,f]
8
>99
>99
99
9
99
lysed asymmetric hydroformylation of vinyl acetate 8,
2,5-dihydrofuran 10 and 2,3-dihydrofuran 11
(Scheme 2).
The catalytic systems were formed in situ by addi-
tion of the diphosphite ligands (L=3, 14–17) to a tol-
[a]
P=18 bar, PCO/PH2 =1, [RhACHTNUTRGNENUG(acac)(CO)2]=0.012 mmol,
8/Rh=400, toluene=5 mL, ligand/Rh=1, T=458C, t=
24 h.
[b]
[c]
[d]
[e]
1
Conversion and regioselectivity measured by H NMR.
% branched product 9.
uene solution of [RhACHTNUGRTNE(NUG acac)(CO)2] (acac=acetylaceto-
Enantioselectivity of 9 measured by GC analysis.
T=208C. Incubation: 24 h at 458C under hydroformyla-
tion condtions.
nate). The substrate was then added and the solution
was introduced into an autoclave. Finally, the auto-
clave was pressurised with 18 bar of CO/H2 mixture
[f]
Ligand/Rh=2.
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Highly Efficient Rhodium Catalysts for the Asymmetric Hydroformylation
Table 2. Rhodium-catalysed asymmetric hydroformylation of
2,5-dhf (10) using diphosphites 14–17.
3, 14–17 are described. When the reaction was carried
out with ligand 3 at 458C with a ligand to Rh ratio of
1, total conversion was achieved with excellent regio-
selectivity to the branched product (up to 99%) and
enantioselectivity of 65% (entry 1). Using the ligand
14, lower enantioselectivity (41%) was obtained al-
though conversion and regioselectivity remained unal-
tered (entry 4). The use of ligand 15 provided compa-
rable activities and regioselectivities to those obtained
with ligand 3, although the enantioselectivities were
slightly lower (ee 60%) (entries 6 and 8). Using the
ligand 16, lower enantioselectivity (48%) was ob-
tained although conversion and regioselectivity re-
mained unaltered (entry 9).
Next, the reaction conditions were optimised with
the catalytic systems Rh/3 and Rh/15, which provided
the higher enantioselectivities in the previous experi-
ments. When the temperature was decreased to 208C
(entries 2 and 6), lower conversion was achieved with
improved regioselectivity (up to 99.9%) and higher
enantioselectivity (ee up to 70%) (entries 1 vs. 2 and 5
vs. 6). Furthermore, when the ligand to rhodium ratio
was increased to 2, the results were very similar al-
though slightly higher enantioselectivities (ee up to
73%) (entries 2 vs. 3 and 6 vs. 7) were obtained. The
ligand 3 provided the highest regioselectivity (99.9%)
and enantioselectivity (73%) of this series of ligands
in the Rh-catalysed asymmetric hydroformylation of
vinyl acetate. When compared with ligand 15, the
lower conversion and enantioselectivity obtained with
the latter ligand showed that an increase in steric hin-
drance at the C-6 position was not beneficial under
these conditions in order to improve the selectivity of
the reaction.
Entry[a]
L
Conv.
[%][b])
% Ald (12/
13)[c]
%
% ee
11[d]
12[e]
1
2
14 100
15 85
15 100
15 100
15 90
16 100
17 100
17 30
79 (81/19)
71 (87/13)
55 (80/20)
98 (86/14)
35 (85/15)
66 (66/34)
96 (96/4)
21
29
45
2
65
34
4
51 (S)
64 (S)
25 (S)
10 (S)
50 (S)
36 (S)
72 (S)
85 (S)
88 (S)
3[f]
4[g]
5[h]
6
7
8[i,j]
9[i,k]
100 (100/0)
100 (100/0)
–
–
17 25
[a]
P=18 bar; PCO/PH2 =1, [RhACHTNUTRGNENUG(acac)(CO)2]=0.012 mmol,
10/Rh=400, toluene=5 mL, Ligand/Rh=2, t=24 h.
[b]
[c]
[d]
[e]
Total conversion measured by 1H NMR.
1
Conversion into aldehydes determined by H NMR.
1
Isomerisation measured by H NMR.
Enantioselectivity of 12 measured by 1H NMR using
EuACTHNUTRGEN(UNG hfc)3.
PCO/PH2 =2.
P=36 bar.
P=3 bar.
[f]
[g]
[h]
[i]
Incubation: 24 h at 458C under hydroformylation condi-
tions.
T=308C.
T=208C.
[j]
[k]
15. When the Rh/17 system was used (entry 7), total
In Table 2, the results obtained for the rhodium-cat- conversion was achieved with 96% chemoselectivity
alysed hydroformylation of 2,5-dihydrofuran 10 using and 96% of regioselectivity to 12. Furthermore, the
the 1,3-diphosphites 14–17 are described. The reaction enantioselectivity was 72%, which is comparable to
conditions were 18 bar of CO/H2 mixture (ratio 1:1) the best results reported for this reaction with ligand
at 458C with a ligand to rhodium ratio of 2.
3.[22] It is noteworthy that the highest chemo- and re-
When the reaction was performed using the ligand gioselectivities reported for this reaction were ob-
14, total conversion of the substrate 10 was achieved tained with ligands 3 and 17, which contain a methyl
with a chemoselectivity to aldehydes of 79%. Apart group at the C-5 position.
from aldehydes 12 and 13, the other reaction product
The results obtained with ligands 14–16 thus indi-
was the 2,3-dihydrofuran 11, formed via isomerisa- cate that the increase in steric hindrance at the C-6
tion. The regioselectivity to product 12 was 81% and position (and therefore at the Rh centre) favours the
a moderate ee (51%) was achieved (entry 1). The di- b-H-elimination from Rh-alkyl intermediates and
phosphite ligand 15 provided lower conversion and consequently, leads to a higher degree of isomerisa-
chemoselectivity than ligand 14. However, this ligand tion. This fact is of importance since in this reaction,
produced higher regioselectivity to 12 with a higher the chemoselectivity and enantioselectivity of product
enantioselectivity (ee up to 64%) (entries 1 vs. 2). The 12 are linked since the hydroformylation of the iso-
catalytic system Rh/16 provided total conversion of merisation product 11 yields the aldehyde 12 with the
the substrate 10, but with a low chemo- and regiose- opposite enantioselectivity than when 12 is produced
lectivity and poor enantioselectivity (36%) (entry 6). by direct hydroformylation of 10.
The larger amount of isomerised product 10 and of al-
In Scheme 6, an attempt for rationalising this fact is
dehyde 13 formed during the catalysis suggested that described. Since the determining step for the regio-
the isomerisation process was favoured with the cata- and enantioselectivity of this reaction is the insertion
À
lytic system Rh/16 when compared to Rh/14 and Rh/ of the alkene insaturation into the Rh H bond, only
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Scheme 6. Schematic representation of the key step for the transfer of chirality during the asymmetric hydroformylation of
2,5-dihydrofuran 10 and 2,3-dihydrofuran 11 using C1-symmetrical bidentate phosphorus ligands coordinated in the eq-eq po-
sitions.
the RhH
N
ACHTUNGTREN(NGNU 2,3-dhf)] com-
products are represented.
When the C2-symmetrical 2,5-dihydrofuran 10 is of diastereoisomeric Rh-alkyl species can therefore
the substrate, there are two possible coordination be formed: the two Rh-2-alkyl species Ic-R and Ic-S,
modes of this molecule to the Rh-hydride complex which after further reaction yield two enantiomers of
(Ia-R and Ia-S, Scheme 3). Insertion of the double tetrahydrofuran-2-carbaldehyde 13 and two Rh-3-
À
bond into the Rh H can therefore yield two diaste- alkyl complexes Ib-R and Ib-S which yield the two
reoisomeric Rh-3-alkyls (IIa-R and IIa-S), which after enantiomers of tetrahydrofuran-3-carbaldehyde 12.
further carbonylation and hydrogenolysis, lead to the
As in the case of 2,5-dihydrofuran 10, the chiral dis-
formation of the two enantiomers of tetrahydrofuran- crimination produced by the disphosphite ligands fa-
3-carbaldehyde 12 (Scheme 6). The chiral nature of vours the formation of one of the enantiomers
the C1-symmetrical diphosphite ligands leads to the formed by hydroformylation for each set of diastereo-
discrimination of one of the two pro-chiral faces of isomeric Rh-alkyl.
the substrate [RhH
G
As this discrimination depends on the structural
and therefore, the formation of one enantiomer of the features of the ligand used, the preferred arrangement
hydroformylation products is favoured. In order to of the Rh-alkyl must be identical to that in the case
match the results obtained in this article (the S-enan- of the 2,5-dhf 10, with the alkyl substituent pointing
tiomer of 12 is mainly produced), the spatial arrange- forward (Scheme 6). In this case, the formation of the
ment around the Rh centre requires the formation of R-enantiomer is therefore favoured.
the Rh-alkyl where the alkyl substituent is pointing
This analysis explains the formation of the opposite
forward, probably corresponding to the less sterically enantiomers of tetrahydrofuran-3-carbaldehyde 12
hindered area of the ligand (represented in white in when the hydroformylation reaction occurs from 2,3-
the Scheme).
or 2,5-dihydrofuran. This schematic representation is
However, when 2,3-dihydrofuran 11 is the sub- in agreement with the results obtained in the Rh-cata-
strate, the lower symmetry of this molecule leads to
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Highly Efficient Rhodium Catalysts for the Asymmetric Hydroformylation
Table 3. Rhodium-catalysed asymmetric hydroformylation of
2,3-dhf (11) using diphosphites 14–17.
lysed asymmetric hydroformylation of 2,5-dihydrofur-
an 10 and 2,3-dihydrofuran 11 described here.
Therefore, to further improve the enantioselectivity,
the degree of isomerisation must be minimised and
the reaction with the Rh/17 catalytic system was thus
performed at lower temperatures (entries 8 and 9).
Under these conditions, moderate conversions (ca.
30%) were obtained with total chemo- and regioselec-
tivity to the aldehyde 12. Furthermore, the enantiose-
lectivity of the reaction increased up to 88% at 208C.
To the best of our knowledge, the Rh/17 system pro-
vides the highest selectivities reported to date for the
hydroformylation of this substrate.
Next, the Rh/15 catalytic system was tested under
higher CO/H2 ratio and higher total pressure. When
the CO/H2 ratio was increased to 2 (entry 3), lower
chemoselectivity to aldehydes and lower enantioselec-
tivity were achieved, although the regioselectivity to
12 remained similar (80%). However, when the total
pressure was increased to 36 bar (entry 4), total con-
Entry[a]
L
Conv. [%][b] % Ald (12/13)[c] % ee of 12[d]
1
2
3
4
14 45
15 25
16 28
17 10
100 (78/22)
100 (78/22)
100 (62/38)
100 (50/50)
83 (R)
84 (R)
61 (R)
–
[a]
P=18 bar, PCO/PH2 =1, [RhACHTNUTRGNENUG(acac)(CO)2]=0.012 mmol,
11/Rh=400, toluene=5 mL, Ligand/Rh=2, T=458C, t=
48 h.
[b]
[c]
[d]
Total conversion measured by 1H NMR.
1
Conversion into aldehydes determined by H NMR.
Enantioselectivity of 12 measured by 1H NMR using
EuACTHNUTRGEN(UNG hfc)3.
version of the substrate was achieved with a clear in- rhodium catalyst (entries 1–3). It is noteworthy that
crease in chemoselectivity to aldehydes. In contrast, the catalytic systems Rh/14 and Rh/15 provided the
the enantioselectivity was found to decrease to 10%. highest enantioselectivity (up to 84%) reported in the
The displacement of the ligand due to the increase in Rh-catalysed asymmetric hydroformylation of 2,3-dhf
pressure to form the unselective [RhH(CO)4] species 11 (entries 1 and 2). Using the catalytic system Rh/17
could explain this result. When the reaction was per- (entry 4), only 10% of conversion was obtained with
formed under 3 bar of pressure using Rh/15 as the poor regioselectivity to 12 (50%) and no enantioselec-
catalytic system (entry 5), 90% conversion was tivity. The best results in the hydroformylation of 11
achieved but with a low selectivity to aldehyde (35%) were thus obtained with Rh/14 and Rh/15 systems
together with a high degree of isomerisation (65%). and the less selective system was Rh/17. This is a
The enantioselectivity was also observed to lower, as striking difference with the results obtained in the hy-
previously described by Nozaki and co-workers under droformylation of 2,5-dihydrofuran 10 for which the
similar conditions.[21]
These results obtained in the asymmetric hydrofor- revealed to be less selective.
best catalytic system was Rh/17 and Rh/14 and Rh/15
mylation of 2,5-dihydrofuran 10 using ligands 14–17
HP-NMR techniques were carried out to investi-
show that that the use of monocyclic carbohydrate gate the coordination mode of the ligands 15 and 17,
backbone improves the performance of the catalyst which provided the best catalytic results using 2,3-dhf
since ligand 17 yielded the best results
and 2,5-dhf as substrates, respectively, in the
As previously mentioned, the production of the op- [RhH(CO)2(L)] complexes.
posite enantiomer of aldehyde 12 can be achieved
through the asymmetric hydroformylation of the 2,3-
dihydrofuran 11 using the same catalytic Rh systems High-Pressure (HP) NMR study
bearing ligands 14–17.
The results obtained in the asymmetric hydrofor- The
hydridorhodium
diphosphite
complexes
mylation of 2,3-dihydrofuran 11 are listed in Table 3. [RhH(CO)2(L)] (L=bidentate ligand) are often ob-
The use of the catalytic system Rh/14 resulted in 45% served as resting states in the hydroformylation reac-
of conversion, 78% of regioselectivity to 12 and enan- tion. Two possible coordination modes of the biden-
tioselectivity of 83% (entry 1). When the catalytic tate ligand can be observed in the tbpy geometry
system Rh/15 was used, lower conversion (25%) was
obtained while the regioselectivity to 12 and the enan-
tioselectivity (84%) remained unchanged (entry 2).
Using the catalytic system Rh/16, 28% conversion
was achieved, with 62% of regioselectivity to 12 and
61% ee (entry 3). These results confirmed that the ac-
tivity, the regioselectivity and the enantioselectivity
were highly affected by the presence of steric bulky
substituents around the coordination sphere of the ligand in the tbpy geometry of the [RhH(CO) CHTUNGTRENNNUG
Figure 2. Two possible coordination modes of the bidentate
2A(P-P)].
Adv. Synth. Catal. 2010, 352, 463 – 477
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asc.wiley-vch.de
469

Aitor Gual et al.
FULL PAPERS
structures (Figure 2).[3,4] The complexes with eq-eq product. The general mechanism for the formation of
(equatorial-equatorial) configuration are expected to these species is described in Scheme 7.[7,10,11]
1
exhibit a JP, H <10 Hz and a JP, P ꢀ250 Hz, whereas for
In the H NMR spectrum of a solution containing
the eq-ax (equatorial-axial) configuration, JP, H ꢀ180– [RhH(CO)2(15)] at room temperature, a broad dou-
200 Hz
served.[3,4,7,10,11,14,30]
One equivalent of the diphosphite ligand (15 or 17)
was added to a 2 mM solution of [Rh(acac)(CO)2] in 156.30 ppm was detected, suggesting that a rapid ex-
and
JP, P ꢀ70 Hz
are
usually
ob- blet at À9.92 ppm (J=3.2 Hz) was observed, suggest-
ing a eq-eq coordination of the ligand (Figure 3).
In the 31P{1H} NMR spectrum, a broad signal at
AHCTUNGTRENNUNG
toluene-d8 at room temperature in a 10-mm NMR change on the NMR timescale was occurring at room
1
tube. In both cases, a rapid change of colour was ob- temperature. Therefore, H and 31P{1H} NMR spectra
served at this stage from colourless to yellow. The were recorded at variable temperatures. At low tem-
NMR tube was pressurised with syngas, shaken for peratures, the 1H NMR signal of the hydride re-
24 h at 458C, placed into the spectrometer and the mained broad whereas at 223 K, the corresponding
NMR spectra were recorded at various temperatures. 31P signals were resolved as two mutually coupled
Under these conditions, signals corresponding to the doublets of doublets at d=153.7 ppm and d=
rhodium hydride species [RhH(CO)2(L)] (L=15 and 161.2 ppm that were assigned to the two inequivalent
17) were readily detected as the only organometallic phosphorus atoms bonded to rhodium. The broadness
of these two signals at temperature above 243 K was
interpreted as a very fast interchange of the coordi-
nated phosphorus atom positions.
To determine the preferred coordination mode of
ligand 15 in [RhH(CO)2(15)], simulations of the
31P{1H} NMR spectrum were performed using the
gNMR V4.0 software. The coupling constants ob-
tained by simulation of the recorded 31P{1H} NMR
spectra at 233, 223 and 203 K are listed in Table 4.
Scheme 7. Mechanism
[RhH(CO)2(L)], with L=bidentate ligand, in the presence
of CO and H2.
for
the
formation
of
the
Figure 3. Selected regions of the 1H and 31P{1H} NMR spectra of complex [RhH(CO)2(15)] in toluene-d8 recorded at variable
temperatures.
470
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ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 463 – 477

Highly Efficient Rhodium Catalysts for the Asymmetric Hydroformylation
1
Table 4. Simulated coupling data of the [RhH(CO)2(15)] at
different temperatures.
nuclear NMR techniques. In the H NMR spectrum at
room temperature, a hydride peak was observed as a
broad quadruplet at À9.93 ppm with JH,P-1 =JH,P-2
=
Entry
1
T [K]
233
d
31P [ppm]
JP, P [Hz]
JRh,P [Hz]
JH,Rh ꢀ4.4 Hz. This coupling constant is in agreement
with an eq-eq disposition of the phosphorus atoms in
the [RhH(CO)2(17)]. In the 31P{1H NMR a broad
signal at 156.2 ppm was detected. This observation
suggested the presence of a rapid exchange on the
NMR timescale.
153.7
160.6
153.8
160.8
154.1
161.2
239.7
239.7
238.9
238.9
239.1
239.1
239.5
240.0
238.9
239.0
239.0
239.1
2
3
223
203
The spectra were therefore recorded at lower tem-
peratures and at 213 K, two broad hydride signals
were detected at À9.62 ppm (DJ1/2 ꢀ40 Hz) and
These coupling constants are JP, P ꢀ239 Hz and JRh,P À9.75 ppm (DJ1/2 ꢀ60 Hz) with a ratio of intensity of
ꢀ240 Hz and are in agreement with an eq-eq coordi- 1:0.6. In the 31P{1H} NMR spectrum, 2 sets of complex
nation of the ligands in the tbpy [RhH(CO)2(15)] spe- multiplets were observed at 165.5 ppm and 155.5 ppm
cies. When this system was analysed by the high pres- (Figure 4). Variable temperature experiments showed
sure Infra-red technique, four frequency bands at that these signals were best resolved at 233 K
2068, 2032, 2010 and 1991 cmÀ1 were observed. These (Figure 4) and, at this temperature, it became evident
frequencies are characteristic of the presence of two that each set of signals corresponded to two pseudo-
dicarbonyl species where the diphosphite ligand is co- triplet 31P signals in the ratio of intensity 1:0.5. Based
ordinated in eq-eq and eq-ax modes.[4,11c] It was there- on these observations, these signals were assigned to
fore concluded that rapid exchange between eq-eq two isomeric forms of [RhH(CO)2(17)].
and eq-ax coordination of the [RhH(CO)2(15)] spe-
cies was occurring at room temperature.
To confirm the identity of these species, simulations
of the 31P{1H} NMR spectra were performed using the
The complex [RhH(CO)2(17)] was also synthesised gNMR V4.0 software. The coupling constants ob-
under the same conditions and characterised by multi- tained by simulation and the chemical shifts recorded
Figure 4. Selected regions of the 1H and 31P{1H} NMR spectra of complex [RhH(CO)2(17)] in toluene-d8 recorded at variable
temperatures.
Adv. Synth. Catal. 2010, 352, 463 – 477
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
471

Aitor Gual et al.
FULL PAPERS
Table 5. Simulated coupling data of the [RhH(CO)2(17)] at
different temperatures.
fully completed. These ligands are shown to be of
very selective in the Rh-catalysed asymmetric hydro-
formylation of vinyl acetate and dihydrofurans. When
vinyl acetate 8 was the substrate, excellent regioselec-
tivities (up to 99.9%) and good enantioselectivities
were achieved using ligands 3 (73%) and 15 (68%).
In the hydroformylation of 2,5-dihydrofuran 10, the
ligand 17 provided excellent chemoselectivity (100%)
and regioselectivity to aldehyde 12 (100%) together
with the highest enantioselectivity (88%) reported to
date for this reaction. When 2,3-dihydrofuran 11 was
the substrate, the use of ligands 14 and 15 provided
excellent chemoselectivity (100%), good regioselectiv-
ity to aldehyde 12 (78%) and the highest enantiose-
lectivity reported to date (84%).
Entry
1
T [K]
233
d
31P [ppm]
JP, P [Hz]
JRh,P [Hz]
152.0
157.9
148.5
160.8
157.0
163.4
153.5
166.4
156.6
164.1
153.6
167.1
237.6
237.6
238.6
230.6
240.0
240.0
240.0
240.0
245.3
245.3
241.6
241.6
236.3
239.0
237.0
236.3
243.3
236.7
236.7
243.2
250.8
239.9
237.8
245.4
2
3
213
193
This study was completed with the HP-NMR and
HP-IR characterisation of the [RhH(CO)2(L)], where
at 233 K, 213 K and 193 K are listed in Table 5. Com- L=15 and 17, demonstrating that both ligands 15 and
paring the calculated coupling constants (JRh,P =JP, P 17 coordinate to the Rh centre in an eq-eq and eq-ax
ꢀ235–240 Hz) with the literature data, the recorded fashion. The complex [RhH(CO)2(15)] was detected
NMR signals were attributed to two isomers of the by NMR as a single isomer with characteristic fea-
complex [RhH(CO)2(17)], which both contain the di- tures of eq-eq coordination. However, the broadening
phosphite ligand in eq-eq position and rapidly inter- of the corresponding signals indicated that this species
change on the NMR timescale.
is rapidly interchanging in solution. Infra-red analysis
In a recent work reported by our group involving confirmed the presence of an equilibrium between eq-
an analogous ligand to 17, such isomers were also de- eq and eq-ax coordinations. In the case of complex
tected by HP-NMR techniques.[25] The presence of [RhH(CO)2(17)], a mixture of two isomers was de-
the less rigid monocyclic backbone in these ligands tected by NMR at low temperature, and both con-
could explain the coexistence of these isomers. tained the diphosphite ligand in an eq-eq fashion. In
Indeed, the increased flexibility of monocyclic furans this case, the increased flexibility of ligand 17ꢄs mono-
when compared to bicyclic structures is well known cyclic backbone is thought to be responsible for the
and documented. These structural features were formation of two conformational isomers of this com-
shown to lead to the formation of various conforma- plex. Infra-red analysis indicated the presence of an
tional isomers which interconvert in solution.[31] The additional equilibrium for each of these conformers
signals observed in this study were therefore assigned with their eq-ax counterparts.
to two conformational isomers of the eq-eq-
[RhH(CO)2(17)] complex. It is thought that upon co-
ordination to the Rh centre, two conformations of the Experimental Section
furan backbone are preferred. Further analysis by
HP-IR techniques revealed the presence of an equi- General Methods
librium between eq-eq and eq-ax-[RhH(CO)2(17)]
All syntheses were performed using standard Schlenk tech-
niques under an N2 atmosphere. Solvents were purified by
standard procedures. All other reagents were used as re-
through the detection of four broad frequency bands
(nCO =2072, 2022, 2010 and 1991 cmÀ1). These comple-
mentary results show that an additional type of equi-
librium is present under CO/H2 pressure. It was there-
fore concluded that each conformer of eq-eq-
[RhH(CO)2(17)] is in equilibrium with its eq-ax coun-
terparts. The fact that only four broad bands were de-
tected by HP-IR is in agreement with the small differ-
ence in frequency that is expected for two conforma-
tional isomers.
ceived. Elemental analyses were performed on a Carlo Erba
EA-1108 instrument. Optical rotations were measured at
1
room temperature in a 10-cm cell. H, 13C{1H} and 31P{1H}
NMR spectra were recorded on a Varian Gemini 400 MHz
spectrometer. Chemical shifts were referenced to SiMe4 (1H
and 13C) as internal standard or H3PO4 (31P) as external
standard. All NMR spectral assignments were determined
1
by COSY and H-13C HSQC spectra. Hydroformylation re-
actions were carried out in a Berghof 100-mL stainless steel
autoclave. Infra-red spectra were recorded on a Bruker
Equinox 55 instrument.
Conclusions
The syntheses of the new chiral diphosphite ligands
14–17 containing a furanoside backbone were success-
472
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ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 463 – 477

Highly Efficient Rhodium Catalysts for the Asymmetric Hydroformylation
O2C
3H, O2C
(CH2)3CH3], 3.58 (m, 2H, 6-H, 6’-H), 3.68 (td, J=6.8,
3.2 Hz, 1H, 5-H), 4.17 (d, J=3.6 Hz, 1H, 3-H), 4.30 (dd, J=
6.8, 3.6 Hz, 1H, 4-H), 4.54 (d, J=3.6 Hz, 1H, 2-H), 5.95 (d,
J=3.6 Hz, 1H, 1-H); 13C NMR (100.6 MHz, CDCl3): d=
G
E
ACHTNUGTRNEN(UGN CH2)3CH3], 1.45 [s,
6-Hydroxy-1,2:3,5-di-O-isopropylidene-a-d-gluco-
furanoside (21)
E
ACHTUNGTRENNUNG
OACHTUNGTRENNUG
1,2;5,6-O-Diisopropylideneglucofuranose (5 g, 19.2 mmol),
Ph3P (8.31 g, 31.7 mmol), and N-bromosuccinimide (5.13 g,
28.8 mmol) were dissolved in toluene (50 mL). The resulting
solution was heated at 908C for 2 h, then cooled, washed
with 5% NaHCO3/H2O and dried (MgSO4). Purification by
flash chromatography (EtOAc/hexane=1/16, Rf =0.25) gave
6-bromo-6-deoxy-1,2:3,5-di-O-isopropylidene-a-d-glucofura-
14.0 [O
24.1 [O2C
[O(CH2)3CH3], 71.2 (C-6), 71.4 (C-5), 71.5 [O
75.0 (C-3), 79.6 (C-4), 84.1 (C-2), 101.0 [O2C(CH3)2], 106.4
(C-1), 112.2 [O2C(CH3)2]; anal. calcd. for C16H28O6: C 60.74,
A
R
ACHTUNGTRENNUNG(CH3)2],
A
R
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
noside as
+31.82 cm3 gÀ1 dmÀ1 (c 1.0 gcmÀ3, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=1.32 [s, 3H, O2C(CH3)2], 1.36 [s, 3H,
O2C(CH3)2], 1.37 [s, 3H, O2C(CH3)2], 1.48 [s, 3H, O2C-
(CH3)2], 3.43 (dd, J=11.2, 7.6 Hz, 1H, 6-H), 3.60 (dd, J=
a
colourless oil; yield: 4.84 g (78%). [a]2D5:
AHCTUNGTRENNUNG
H 8.92; found: C 60.68, H 9.00.
AHCTUNGTRENNUNG
1,2:3,5-Di-O-isopropylidene-6-O-butyl-a-d-glucofurano-
side (700 mg, 2.2 mmol) was dissolved in AcOH/H2O (65%,
10 mL), and the mixture was stirred at 408C for 10 h. After
cooling to room temperature, the solution was co-evaporat-
ed with EtOH and toluene at reduced pressure to afford the
diol 22 as a white powder; yield: 446 mg (73%). [a]2D5:
+1.32 cm3 gÀ1 dmÀ1 (c 1.0 gcmÀ3, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=0.91 [t, J=7.4 Hz, 3H, O-
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
11.0, 3.4 Hz, 1H, 6’-H), 3.73 (td, J=7.2, 3.2 Hz, 1H, 5-H),
4.22 (d, J=4.4 Hz, 1H, 3-H), 4.31 (dd, J=7.2, 4.0 Hz, 1H, 4-
H), 4.58 (d, J=3.6 Hz, 1H, 2-H), 5.98 (d, J=3.6 Hz, 1H, 1-
H); 13C NMR (100.6 MHz, CDCl3): d=23.9 [O2C
ACHTUNGTRENNUNG
24.0 [O2CACHTUNGTRENNUNG(CH3)2], 26.6 [O2CACHTUTNGNERNUG(CH3)2], 27.3 [O2CACTUHNGTRENNUGN
A
R
ACHTUGNTRENUN(GN CH3)2], 1.36 [s, 2H, O-
E
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
for C12H19BrO5 (323.18): C 44.60, H 5.93; found: C 44.28, H
6.12.
NaNO2 (0.84 g, 12.4 mmol) was added to a solution of 6-
bromo-6-deoxy-1,2:3,5-di-O-isopropylidene-a-d-glucofuran-
G
ACHTUNGTRENNUNG
4.4 Hz, 1H, 6-H], 3.69 (dd, J=10, 3.6 Hz, 1H, 6’-H), 4.05
(dd, J=6.8, 3.2 Hz, 1H, 3-H), 4.15 (m, 1H, 5-H), 4.32 (d,
J=3.2 Hz, 1H, 4-H), 4.52 (d, J=3.6 Hz, 1H, 2-H), 5.95 (d,
J=4.0 Hz, 1H, 1-H); 13C NMR (100.6 MHz, CDCl3): d=
ACHTUNGTRENNUNGoACHTUNGTRENNUNGside (2 g, 6.2 mmol) in DMF (20 mL), and the mixture was
stirred at 708C for 4 h. The reaction was monitored by TLC
(1:1 hexane-EtOAc) until all starting material was con-
sumed. Purification by flash chromatography (EtOAc/
hexane=1/1, Rf =0.40) gave the final product 21 as a colour-
less oil; yield: 580 mg (36%). [a]2D5: +29.49 cm3 gÀ1 dmÀ1 (c
14.0 [O
26.9 [O2C
6), 71.7 [O
105.0 (C-1), 111.8 [O2CAHCTUNGTRENNUNG
G
CAHUTGTNRENN(GU CH2)3CH3], 26.3 [O2CACHTUNGTRENNUNG(CH3)2],
E
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
56.51, H 8.75; found: C 56.47, H 8.80.
1
1.0 gcmÀ3, CH2Cl2); H NMR (400 MHz, CDCl3): d=1.29 [s,
3H, O2C
ACHTUNGTRENNUNG(CH3)2], 1.33 [s, 6H, O2CAHCUTGNTRENN(GUN CH3)2], 1.45 [s, 3H, O2C-
ACHTUNGTRENNUNG
1H, 6-H), 4.15 (d, J=3.6 Hz, 1H, 3-H), 4.33 (dd, J=6.8,
3.6 Hz, 1H, 4-H), 4.54 (d, J=4.0 Hz, 1H, 2-H), 5.95 (d, J=
4.0 Hz, 1H, 1-H); 13C NMR (100.6 MHz, CDCl3): d=24.1
1,2-O-Isopropylidene-6-O-(1,1-dimethyl-3-butene)-a-
d-glucofuranoside (24)
To a solution of 1,2;5,6-O-diisopropylideneglucofuranose
(1.76 g, 6.63 mmol) in CH2Cl2 (250 mL) cooled at À108C
Me3SiAllyl (4.24 mL, 26.5 mmol) and BF3·Et2O (1.51 mL,
11.9 mmol) were added. The reaction mixture was stirred at
À108C for 2 h, and quenched by careful addition to saturat-
ed NaHCO3/H2O (50 mL). The aqueous layer was extracted
with CH2Cl2 (3ꢅ50 mL), and the combined organic phases
were washed (brine) and dried (MgSO4). Purification by
flash chromatography (EtOAc, Rf =0.42) gave the product
[O2C
[O2C
N
ACHUTNTGRNE(NUG CH3)2], 26.6 [O2CACHUTNGTRNE(NUGN CH3)2], 27.2
84.0 (C-2), 101.0 [O2CACHTUNGTRENNUNG
ACHTUNGTRENNUNG
1,2-O-Isopropylidene-6-O-butyl-a-d-glucofuranoside
(22)
To a solution of 6-hydroxy-1,2:3,5-di-O-isopropylidene-a-d-
glucofuranoside (520 mg, 2.0 mmol) in THF (15 mL) at
room temperature, NaH (320 mg, 8.0 mmol) was added. The
reaction mixture was stirred at room temperature for 1 h
and butyl bromide (308 mg, 2.2 mmol) was added together
with catalytic quantities of 18-crown-6 ether. The reaction
mixture was stirred overnight at room temperature and
quenched by careful addition of H2O. The aqueous layer
was extracted with CH2Cl2 (3ꢅ50 mL), and the combined
organic phases were washed with brine and dried with
MgSO4. Purification by flash chromatography (EtOAc/
hexane=1/3, Rf =0.70) gave 1,2:3,5-di-O-isopropylidene-6-
24 as a
colourless oil; yield: 802 mg (40%). [a]2D5:
+0.24 cm3 gÀ1 dmÀ1 (c 1.0 gcmÀ3, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=1.18 [d, J=5.6 Hz, 6H, OC-
A
ACHTUGNTRENUN(NG CH3)2], 1.48 [s, 3H,
AHCTUNGTRENNUNG
(dd, J=9.5, 5.2 Hz, 1H, 6-H), 3.66 (dd, J=9.3, 3.0 Hz, 1H,
6-H) , 4.08 (d, J=4.2 Hz, 1H, 4-H), 4.35 (d, J=2.4 Hz, 1H,
3-H), 4.53 (d, J=3.6 Hz, 1H, 2-H), 5.05 (m, 1H, 5-H), 5.08
(m, 2H, CH2CH=CH2), 5.82 (m, 1H, CH2CH=CH2), 5.95 (d,
J=3.6 Hz, 1H, 1-H); 13C NMR (100.6 MHz, CDCl3): d=
25.3 [OC
CH2], 26.3 [O2C
CH2), 62.6 (C-6), 69.7 (C-5), 75.5 [OC
76.0 (C-4), 80.3 ( C-3), 85.2 (C-2)), 105.0 (C-1), 111.7 [O2C-
(CH3)2], 117.9 (CH2CH=CH2). 134.3 (CH2CH=CH2); anal.
calcd. for C15H26O6: C 59.58, H 8.67; found: C 59.50, H 8.70.
A
ACHTNUGERTN(NUGN CH3)2 CH2CH=
A
ACHTUNGTRENNUNG
O-butyl-a-d-glucofuranoside as
a
colourless oil; yield:
ACHTUNGTRENNUNG
525 mg (83%). [a]2D5: +18.68 cm3 gÀ1 dmÀ1 (c 1.0 gcmÀ3,
1
CH2Cl2); H NMR (400 MHz, CDCl3): d=0.88 [t, J=7.6 Hz,
ACHTUNGTRENNUNG
3H, OACHTUNGTRENNUNG(CH2)3CH3], 1.29 [s, 3H, O2CCAHTUNGTERN(NUGN CH3)2], 1.33 [s, 3H,
Adv. Synth. Catal. 2010, 352, 463 – 477
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
473

Aitor Gual et al.
FULL PAPERS
uene, Rf =0.60); yield: 749 mg (0.65 mmol, 65%). [a]2D5:
+98.78 cm3 gÀ1 dmÀ1 (c 1.0 gcmÀ3, CH2Cl2); 1H NMR
1,2-O-Isopropylidene-6-O-(1,1-dimethyl-3-butyl)-a-d-
glucofuranoside (25)
(CDCl3, 400 MHz): d=0.94 [m, 3H, O
3H, O2C(CH3)2], 1.26 [m, 41H, O2C(CH3)2, O
(CH3)3], 1.38 [m, 38H, O(CH2)3CH3, C(CH3)3], 3.14 [m,
2H, O(CH2)3CH3], 3.64 (d, J=11.2 Hz, 1H, 6-H), 3.61 (dd,
ACHTUNGTRENNUNG
To a solution of 1,2-O-isopropylidene-6-O-(1,1-dimethyl-3-
butene)-a-d-glucofuranoside (802 mg, 2.65 mmol) in THF
(4 mL), a catalytic amount of Pd/C (0.1 mmol) was added.
The reaction mixture was stirred for 12 h under 1 bar of H2.
The H2 pressure was purged and the mixture was filtered
though celite to obtain the diol 25 as a white powder; yield:
800 mg (99%). [a]2D5: +11.50 cm3 gÀ1 dmÀ1 (c 1.0 gcmÀ3,
A
R
ACHTUNGTRENNUNG
C
N
N
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
J=11.2, 4.8 Hz, 1H, 6’-H), 4.02 (m, 1H, 2-H), 4.31 (m, 1H,
4-H), 4.57 (m, 1H, 5-H), 4.74 (m, 1H, 3-H), 5.37 (d, J=
3.2 Hz, 1H, 1-H), 7.36–7.03 (m, 8H, aromatic); 13C NMR
(CDCl3, 100.6 MHz): d=14.2 [O
(CH2)3CH3], 21.7 [O(CH2)3CH3], 26.7 [O2C
[O2C(CH3)2], 32.0–31.5 [C(CH3)3], 35.6–34.8 [C
(C-6), 71.3 [O(CH2)3CH3], 72.2 (C-5), 77.4 (C-4), 78.9 (C-3),
ACHTUNGTRENNUNG
1
CH2Cl2); H NMR (400 MHz, CDCl3): d=0.91 (t, J=7.2 Hz,
A
R
ACHTUNGTRENNUNG
3H, CH2CH2CH3), 1.18 [m, 6H, OC
1.32 [s, 3H, O2C(CH3)2], 1.44 (m, 4H, CH2CH2CH3), 1.49 [s,
3H, O2C(CH3)2], 3.45 (dd, J=9.2, 4.8 Hz, 1H, 6ꢄ-H), 3.64
ACTHGNUERTN(NUNG CH3)2CH2CH2CH3],
A
R
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
84.3 (C-2), 105.0 (C-1), 112.0 [O2CACTHNUTRGNEUNG(CH3)2], 146.9–124.2 (aro-
(dd, J=9.4, 2.6 Hz, 1H, 6-H) , 4.09 (d, J=2.0 Hz, 1H, 4-H),
4.35 (d, J=2.0 Hz, 1H, 3-H), 4.55 (d, J=3.6 Hz, 1H, 2-H),
5.96 (d, J=3.6 Hz, 1H, 1-H); 13C NMR (100.6 MHz,
CDCl3): d=14.5 (CH2CH2CH3), 17.0 (CH2CH2CH3), 25.2
matic); 31P NMR (CDCl3, 161.97 MHz): d=145.1 (d, J=
43.7 Hz), 146.1 (d, J=43.7 Hz); anal. calcd. for C69H102O10P2:
C 71.85, H 8.91; found: C 71.75, H 9.05.
3,5-Bis-O-[(3,3’:5,5’-tetra-tert-butyl-1,1’-biphenyl-2,2’-di-
yl)phosphite]-6-O-isopropyl-1,2-O-isopropylidene-a-d-gluco-
furanose (15): The synthesis of diphosphite 15 was complet-
ed according to the general procedure previously described
starting from diol 23. The product was isolated as a white
solid after purification by flash column chromatography (tol-
uene, Rf =0.60); yield: 569 mg (0.50 mmol, 50%). [a]2D5:
+138.54 cm3 gÀ1 dmÀ1 (c 1.0 gcmÀ3, CH2Cl2); 1H NMR
(CDCl3, 400 MHz): d=0.94 [dd, J=6.4, 9.4 Hz, 6H, OCH-
[OC
[O2C
(C-6), 69.5 (C-5), 75.6 [OC
80.1 (C-3), 85.0 (C-2)), 104.8 (C-1), 111.5 [O2CAHCTUNGTRENNUNG
A
ACTHUGNNERTN(NUG CH3)2CH2CH2CH3], 26.0
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
calcd for C15H28O6: C 59.19, H 9.27; found: C 59.10, H 9.30.
General Procedure for Synthesising Diphosphite
Ligands
A
R
ACHTUNGTRENNUNG(CH3)2,
A solution of the appropriate diol (1.0 mmol), previously
azeotropically dried with toluene (3ꢅ1 mL), in dry and de-
gassed toluene (10 mL) and cooled to 08C, was slowly
added to a solution of phosphorochloridite (2.1 mmol), syn-
thesised in situ by standard procedures,[29] in dry and de-
gassed pyridine (1.5 mL). The mixture was allowed to warm
to room temperature and stirred overnight. The mixture was
then filtered to eliminate the pyridine salts, and the filtrate
was concentrated to dryness. The white foam obtained was
purified by flash chromatographic techniques over nitrogen.
3,5-Bis-O-[(3,3’:5,5’-tetra-tert-butyl-1,1’-biphenyl-2,2’-di-
yl)phosphite]-6-deoxy-1,2-O-isopropylidene-a-d-glucofura-
nose (3): The synthesis of diphosphite 3 was completed ac-
cording to the general procedure previously described start-
ing from diol 20. The product was isolated as a white solid
after purification by flash column chromatography (toluene,
Rf =0.63); yield: (628 mg, 0.58 mmol (58%). [a]2D5:
+117.36 cm3 gÀ1 dmÀ1 (c 1.0 gcmÀ3, CH2Cl2); 1H NMR
C
AHCTUNGTRENNUNG
G
ACHTUNGTRENNUNG
4.41 (dd, J=2.4, 8.4 Hz, 1H, 5-H), 4.60 (m, 1H, 3-H), 4.81
(dd, J=6.0, 2.4 Hz, 1H, 4-H), 5.46 (d, J=3.2 Hz, 1H, 1-H),
7.45–7.13 (m, 8H, aromatic); 13C NMR (CDCl3, 100.6 MHz):
d=22.0 [OCH
(CH3)2], 26.9 [O2C
34.7 [C(CH3)3], 35.6 [C
(CH3)2], 72.3 (C-5), 77.5 (C-4), 78.9 (C-3), 84.3 (C-2), 105.0
(C-1), 112.0 [O2C
(CH3)2], 146.9–124.2 (aromatic); 31P NMR
G
ACHTUNGTRENNUNG
R
G
G
ACHTUNGTRENNUNG
N
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
(CDCl3, 161.97 MHz): d=145.2 (d, J=47.9 Hz), 146.3 (d,
J=48.1 Hz); anal. calcd. for C68H100O10P2: C 71.68, H 8.85;
found: C 71.45, H 9.00.
3,5-Bis-O-[(3,3’:5,5ꢀ-tetra-tert-butyl-1,1’-biphenyl-2,2’-di-
yl)phosphite]-6-O-(1,1-dimethyl-3-butane)-1,2-O-isopropyli-
dene-a-d-glucofuranose (16): The synthesis of diphosphite
16 was completed according to the general procedure previ-
ously described starting from diol 25. The product was iso-
lated as a white solid after purification by flash column
chromatography (toluene, Rf =0.60); yield; 590 mg
(0.50 mmol, 50%). [a]2D5: +112.18 cm3 gÀ1 dmÀ1 (c 1.0 gcmÀ3,
(CDCl3, 400 MHz): d=1.10 [s, 3H, O2C
ACHTUNGTRENNUNG
6.0 Hz, 3H, 6-H), 1.48–1.32 [s, 75H, C(CH3)3, O2CACHTNUGTRENNUNG
G
4.07 (m, 1H, 2-H), 4.75 (dd, J=8.2, 2.6 Hz, 1H, 4-H), 4.73
(m, 1H, 5-H), 4.81 (dd, J=6.4, 2.4 Hz, 1H, 3-H), 5.48(d,
J=3.6 Hz, 1H, 1-H), 7.45–7.16 (m, 8H, aromatic); 13C NMR
1
CH2Cl2); H NMR (CDCl3, 400 MHz): d=0.94 (t, J=6.8 Hz,
3H, CH2CH2CH3), 1.12 [s, 3H, O2C
O2C(CH3)2, CH2CH2CH3, (CH3)3], 1.53 [s, 38H,
CH2CH2CH3, C(CH3)3], 3.64 (dd, J=10.4, 4.0 Hz, 1H, 6-H),
3.73 (d, J=10.4 Hz, 1H, 6’-H), 4.02 (d, J=3.2 Hz, 1H, 2-H),
4.49 (dd, J=8.4, 2.4 Hz, 1H, 4-H), 4.59 (m, 1H, 5-H), 4.83
(d, J=3.2 Hz, 1H, 3-H), 5.46 (d, J=3.6 Hz, 1H, 1-H), 7.48–
7.17 (m, 8H, aromatic); 13C NMR (CDCl3, 100.6 MHz): d=
14.8 (CH2CH2CH3), 17.1 (CH2CH2CH3), 21.7 (CH2CH2CH3),
26.2 [O2C
35.7–34.7 [C
[OC(CH3)2CH2CH2CH3], 74.8 (C-5), 76.9 (C-4), 78.6 (C-3),
84.4 (C-2), 105.1 (C-1), 112.0 [O2C(CH3)2], 146.9–124.1 (aro-
matic); 31P NMR (CDCl3, 161.97 MHz): d=145.8 (d, J=
ACHTUGNTRENUN(NG CH3)2], 1.40 [s, 41H,
(CDCl3, 100.6 MHz): d=19.4 (C-6), 26.3 [O2C
[O2C(CH3)2], 31.5–31.2 [C(CH3)3], 35.4–34.6 [C
(C-5), 76.2 (C-3), 83.0 (C-4), 84.2 (C-2), 104.7 (C-1), 111.6
[O2C
(CH3)2], 146.8–124.0 (aromatic); 31P NMR (CDCl3,
ACHTUNGTRENNUNG
N
CACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
161.97 MHz): d=144.4(d, J=34.0 Hz), 145.6 (d, J=35.3 Hz);
anal. calcd. for C65H94O9P2: C 72.19, H 8.76; found: C 72.00,
H 8.95.
3,5-Bis-O-[(3,3’:5,5’-tetra-tert-butyl-1,1’-biphenyl-2,2’-di-
yl)phosphite]-6-O-butyl-1,2-O-isopropylidene-a-d-glucofura-
nose (14): The synthesis of diphosphite 14 was completed
according to the general procedure previously described
starting from diol 22. The product was isolated as a white
solid after purification by flash column chromatography (tol-
A
ACHTUNTGRENNGU(CH3)2], 31.8–31.2 [CACHTUNGTRENNUNG(CH3)3],
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
474
asc.wiley-vch.de
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 463 – 477

Highly Efficient Rhodium Catalysts for the Asymmetric Hydroformylation
45.8 Hz), 146.7 (d, J=50.2 Hz); anal. calcd. for C71H106O10P2:
C 72,17, H 9,04; found: C 72.05, H 9.20.
6.8 Hz, 3H,
(CH2)15CH3], 1.30 [m, 36H, C
(CH3)3], 3.10 [m, 1H, O(CH2)15CH3], 3.37 [m, 1H, O-
(CH2)15CH3], 3.43 (dd, J=4.4, 9.2 Hz, 1H, 1-H), 3.48 (d, J=
4 Hz, 1H, 1’-H), 3.61 (d, J=9.6 Hz, 1H, 4-H), 3.88 (dd, J=
9.2, 1.6 Hz, 1H, 2-H), 4.83 (m, 1H, 5-H), 5.02 (m, 1H, 3-H),
7.56–7.15 (m, 8H, aromatic); 13C NMR (100.6 MHz, tolu-
OACHTUNGTRENNUNG
G
E
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
1,4-Anhydro-3,5-bis-O-[(3,3’:5,5ꢀ-tetra-tert-butyl-1,1’-bi-
phenyl-2,2’-diyl)phosphite]-6-deoxy-2-O-sec-hexadecyl-d-
glucitol (17): The synthesis of diphosphite 17 was completed
according to the general procedure previously described
starting from diol 26. The product was isolated as a white
solid after purification by flash column chromatography (tol-
uene, Rf =0.73); yield: 925 mg (0.74 mmol, 74%). [a]2D5:
+92.90 cm3 gÀ1 dmÀ1 (c 1.0 gcmÀ3, CH2Cl2); 1H NMR
(CDCl3, 400 MHz): d=0.90 (t, J=6.4 Hz, 3H, O-hexadecyl),
1.25 (d, 3H, J=6.0 Hz, 6-H), 1.29 (s, 26H, O-hexadecyl),
ACHTUNGTRENNUNG
ene-d8): d=14.0 [O
(CH2)15CH3], 25.9 [O(CH2)15CH3], 29.2 [O
[O(CH2)15CH3], 30.9 [C(CH3)3], 31.2 [O(CH2)15CH3], 35.8–
34.6 [C(CH3)3], 68.1 (C-5), 69.7 [O(CH2)15CH3], 71.5 (C-1),
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
74.7 (C-3), 81.9 (C-4), 82.2 (C-2), 149.2–125.2 (aromatic);
31P NMR (161.97 MHz, toluene-d8): d=154.2 (br m); IR:
nCO =2072, 2022, 2010, 1991 cmÀ1.
1.36 [m, 36H, CACHTUNGTRENNUNG(CH3)3], 1.46 [m, 36H, CAHCTUNGTREN(NUGN CH3)3], 3.23 (m,
1H, O-hexadecyl), 3.35 (m, 1H, O-hexadecyl), 3.55 (m, 2H,
H-1’, H-1), 3.70 (dd, J=10.0, 4.4 Hz, 1H, 4-H), 3.90 (dd, J=
7.4, 2.2 Hz, 1H, 2-H), 4.76 (m, 1H, 5-H), 4.84 (m, 1H, 3-H),
7.44–6.14 (m, 8H, aromatic); 13C NMR (CDCl3, 100.6 MHz):
d=14.3 (O-hexadecyl), 19.7 (C-6), 22.9 (O-hexadecyl), 26.3
(O-hexadecyl), 29.6 (O-hexadecyl), 29.8 (O-hexadecyl), 31.6
Hydroformylation Experiments
In a typical experiment, the autoclave was purged 3 times
with CO. The solution was formed from [RhACTHUNTRGNE(UNG acac)(CO)2]
(3.1 mg, 0.012 mmol), the corresponding quantities of di-
phosphite and the substrate (4.8 mmol) in toluene (5 mL).
The autoclave was pressurised to the appropriate pressure
of CO/H2. After the desired reaction time, the autoclave
was cooled to room temperature and depressurised. Conver-
sion and regioselectivity of the hydroformylation of vinyl
acetate 8 were determined immediately after catalysis by
1H NMR analysis of the crude reaction without evaporation
of the solvent. The enantiomeric excess of 9 was measured
by GC analysis in a Hewlett–Packard HP 5890A gas chro-
matograph (split/splitless injector, J&W Scientific, FS-Beta-
dex 25 m column, internal diameter 0.2 mm, film thickness
0.33 mm, oven temperature=658C, carrier gas: 50 kPa He,
FID detector): (S)-isomer 9=12.8 min, (R)-isomer 9=
13.3 min.[5a,14b] Conversion and selectivity of the hydroformy-
lation of dihydrofurans 10 and 11 were determined immedi-
[CACHTUNGTRENNUNG(CH3)3], 31.8 (O-hexadecyl), 35.6–34.9 [CAHCUTNGTREN(NUGN CH3)3], 69.7
(C-5), 70.0 (O-hexadecyl), 72.1 (C-1), 75.7 (C-3), 83.7 (C-4),
84.2 (C-2), 146.8–124.2 (aromatic); 31P NMR (CDCl3,
161.97 MHz): d=144.6 (d, J=45.8 Hz), 147.5 (d, J=
46.9 Hz); anal. calcd. for C78H122O8P2: C 74.96, H 9.84;
found: C 74.75, H 10.00.
In situ HP-NMR and HP-IR experiments
In a typical HP-NMR experiment, a sapphire tube (ø=
10 mm) was filled under argon with
a solution of
[Rh(acac)(CO)2] (2.10–2 mM) and ligand (molar ratio PP/
ACHTUNGTRENNUNG
Rh=1.1) in toluene-d8 (2 mL). The solution was analysed
1
by H and 31P NMR. Next, the HP-NMR tube was purged 3
times with CO and pressurised to the appropriate pressure
of CO/H2. After 24 h at 458C, the solution was analysed by
multinuclear NMR spectroscopy. The HP-IR experiments
were carried out in an SS316 50 mL autoclave equipped
with an IRTRAN window (ZnS, transparent up to 70 cmÀ1,
10 mm i.d., optical path length 0.4 mm), a mechanical stir-
rer, a temperature controller, and a pressure device. In a
1
ately after catalysis by H NMR analysis of the crude reac-
tion without evaporation of the solvent. The determination
of the enantiomeric excess and absolute configuration of the
methyl tetrahydro-3-furoate derived from 12 was measured
1
by H NMR using Eu
ACHTUNGRTEN(NUNG hfc)3 by previously described proce-
dures.[21,22]
typical experiment, a toluene solution of [RhACHTUNTRGENUG(N acac)(CO)2]
(0.0013 mM) and ligand (molar ratio PP/Rh=1.1) were in-
troduced in the IR autoclave. The autoclave was purged
twice with CO, pressurised to 18 bar of CO/H2 and heated
to 458C. The reaction was usually completed within 3–4 h.
Determination of the Absolute Configuration and
Enantiomeric Excess of 12
The reaction mixture was diluted with acetone and cooled
with an ice bath. To this mixture, the Jones reagent was
slowly added, and the mixture was stirred at room tempera-
ture overnight. The reaction mixture was treated with
NaHSO3. After disappearance of the orange colour, the in-
soluble material was filtered off. Then the filtrate was con-
centrated and the residue was diluted with brine and ex-
tracted three times with diethyl ether. The combined organic
layers were washed twice with brine, dried over MgSO4, and
then concentrated to give the corresponding tetrahydro-3-
1
Characterisation of [RhH(CO)2(15)]: H NMR (400 MHz,
toluene-d8]): d=À9.92 (d, J=3.2 Hz, 1H), 0.94 [dd, J=6.4,
11.6 Hz, 6H, OCHACHTUNGTRENNUNG(CH3)2], 1.05 [s, 3H, O2CCAHTUNTGREN(NUGN CH3)2], 1.27 [s,
39H, O2C
N
ACHTUNTGERNUNG(CH3)3], 1.70 [s, 36H, CACHUTNGTERN(NUGN CH3)3], 3.29 [m,
1H, OCHACHTUNGTRENNUNG
4.37 (d, J=4.0 Hz, 1H, 5-H), 4.69 (m, 1H, 3-H), 4.83 (m,
1H, 4-H), 5.58 (d, J=4.0 Hz, 1H, 1-H), 7.63–7.29 (m, 8H,
aromatic); 13C NMR (100.6 MHz, toluene-d8): d=21.8
[OCH
[O2C(CH3)2], 31.6 [C
(CH3)3], 35.8 [C(CH3)3], 68.3 (C-6), 71.9 [OCH
(C-5), 76.9 (C-4), 78.4 (C-3), 84.8 (C-2), 105.8 (C-1), 112.8
(O2C(CH3)2), 148.3–123.2 (aromatic);
31P NMR
A
R
ACHTUGNTRNEN(UNG CH3)2], 26.7
1
A
E
U
furoic acid. H NMR (CDCl3, 400 MHz): d=2.15 (m, 2H, 4-
A
E
U
H), 3.15 (m, 1H, 3-H), 3.85 (m, 1H, 5-H), 3.90 (m, 1H, 5’-
H), 4.00 (d, J=7.2 Hz, 1H, 2-H), 10.34 (br s, 1H).
E
According to reported methods, to a mixture of crude
acid and SiO2Cl, dry methanol was added dropwise at 08C
under nitrogen atmosphere.[32] The reaction mixture was
stirred overnight. The crude mixture was filtered and solvent
was evaporated under reduced pressure to afford the methyl
(161.97 MHz, toluene-d8): d=156.1 (br m); IR: nCO =2068,
2032, 2010, 1991 cmÀ1.
Characterisation of [RhH(CO)2(17)]: H NMR (400 MHz,
1
toluene-d8): d=À9.93 (ddd, J=4.4 Hz, 1H), 0.89 [t, J=
Adv. Synth. Catal. 2010, 352, 463 – 477
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
475

Aitor Gual et al.
FULL PAPERS
tetrahydro-3-furoate
derivative.
1H NMR
(CDCl3,
[11] a) G. J. H. Buisman, M. E. Martin, E. J. Vos, A. Kloot-
wijk, P. C. J. Kamer, P. W. N. M. van Leeuwen, Tetrahe-
dron: Asymmetry 1995, 6, 719–738; b) O. Pꢂmies, G.
Net, A. Ruiz, C. Claver, Tetrahedron: Asymmetry 2000,
11, 1097–1108; c) M. Diꢈguez, O. Pꢂmies, A. Ruiz, S.
Castillꢀn, C. Claver, Chem. Eur. J. 2001, 7, 3086–3094;
d) M. Diꢈguez, O. Pꢂmies, A. Ruiz, C. Claver, New. J.
Chem. 2002, 26, 827–833.
400 MHz): d=2.14 (m, 2H, 4-H), 3.08 (m, 1H, 3-H), 3.67 (s,
3H, OCH3), 3.71 (s, 3H), 3.83 (m, 1H, 5-H), 3.86 (m, 1H,
5’-H), 3.93 (d, J=8.4 Hz, 1H, 2-H).
The enantiomeric excess was determined by 1H NMR
spectroscopy using EuACTHNUTRGNEUNG(hfc)3 as the chiral shift reagent [(R)-
methyl tetrahydro-3-furoate: d=4.52 and (S)-methyl tetra-
hydro-3-furoate: d=4.55).
[12] a) C. J. Cobley, J. Klosin, C. Qin, G. T. Whiteker, Org.
Lett. 2004, 6, 3277–3280; b) C. J. Cobley, K. Gardner, J.
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[13] a) S. Castillꢀn, C. Claver, Y. Dꢁaz, Chem. Soc. Rev.
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Acknowledgements
We are grateful to the Spanish Ministerio de Educaciꢀn y
Ciencia (CTQ2007-62288/BQU, CTQ2005-03124), Consolid-
er Ingenio 2010, CSD2006–0003, to the Juan de la Cierva fel-
lowship to C. Godar) and the Generalitat de Catalunya
(2005SGR007777) Distinction for Research Promotion, 2003
C.C. for financial support. We are grateful to the Spanish
Ministerio de Educaciꢀn y Ciencia for awarding a research
grant to Aitor Gual (FPU program/AP2005–1263).
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