Bis(phosphite) ligands with distal regulation: Application in rhodium-mediated asymmetric hydroformylations

Article abstract of DOI:10.1002/chem.201203677

Small amounts of achiral polyether binders are employed to enhance the enantioselectivity of the hydroformylation of an array of diversely substituted substrates (increase of up to 62 % ee for vinyl acetate) mediated by chiral rhodium complexes derived from the α,ω-bis(phosphite)-polyether ligands 1. To the best of our knowledge, this study represents an unprecedented successful example of the positive regulation of enantioselectivity in hydroformylations.

Full text of DOI:10.1002/chem.201203677

DOI: 10.1002/chem.201203677
Bis(phosphite) Ligands with Distal Regulation: Application in
Rhodium-mediated Asymmetric Hydroformylations
Ignasi Mon,[a] D. Amilan Jose,[a] and Anton Vidal-Ferran*[a, b]
Abstract: Small amounts of achiral polyether binders are employed to enhance the
enantioselectivity of the hydroformylation of an array of diversely substituted sub-
strates (increase of up to 62% ee for vinyl acetate) mediated by chiral rhodium
complexes derived from the a,w-bis(phosphite)–polyether ligands 1. To the best of
our knowledge, this study represents an unprecedented successful example of the
positive regulation of enantioselectivity in hydroformylations.
Keywords: alkenes
catalysis · enantioselectivity · hydro-
formylation · rhodium
·
asymmetric
Introduction
signed to reduce the synthetic efforts for ligand variation
and have enabled the generation of ligand libraries with un-
precedented ease.
The greatest challenge in asymmetric homogeneous catalysis
has been the design and development of enantioselective
catalysts that can efficiently mediate a given chemical trans-
formation with high selectivity and broad substrate scope.
Ligand-tuning in asymmetric catalysis has facilitated the
rapid development of efficient catalytic systems for broad
arrays of substrates.[1] Ligand design incorporates several in-
dependent modules or molecular fragments assembled
around a chiral skeleton. These modules are designed to in-
fluence the catalytic site; the sterics and electronics of the
constituent molecular fragments (or ligand modules) are
considered to be the input parameters for the catalyst opti-
mization process. Modification of the steric and electronic
properties of these ligand modules enables higher-perform-
ing catalytic systems (i.e., those offering a higher conversion
and/or enantioselectivity for the widest possible substrate
scope). Modular approaches to asymmetric catalysis have
enabled major advances in asymmetric catalysis for nearly
every conceivable catalytic transformation. However, this
strategy suffers from an important drawback: the attach-
ment of diverse molecular fragments to the ligand skeleton
using covalent chemistry is laborious and may involve signif-
icant synthetic efforts. Combinatorial or high-throughput
synthetic strategies that utilize either standard covalent
chemistry[2] or supramolecular interactions[3] have been de-
Allosteric modulation, or allosterism, consists of the mod-
ification of a biologically active site by the interaction of an
external unit (effector) with a distinct specific regulation
site. This process is very common in living organisms, in
which it enables structural and functional regulation.[4] The
mechanism of action is based on binding of the effector to
the regulation site, which causes a conformational change to
the catalytic site and a modification of its catalytic proper-
ties. Since Rebekꢀs pioneering design of artificial allosteric
receptors,[5] other non-natural systems have been designed
and applied to control binding or catalysis.[6] However, ex-
amples of enantioselective catalysts with an achiral regula-
tion site are scarce.[7] The reported examples were found to
be functional in the enantioselective ring opening of meso-
epoxides,[7a,b] and in the asymmetric hydrogenation[7c] and
hydroformylation[7d,e] of a limited set of alkenes (b-aryl-a-
(acylamino)acrylates[7c] and trans-2-octene,[7d,e] respectively).
As a continuation of our ongoing endeavor to regulate
binding properties or catalytic activity in chiral supramolec-
ular entities,[8] we report herein our results of the use of the
conformationally transformable bis(phosphites) 1 in asym-
metric hydroformylations. In combination with the well-
known bis(phosphite) binding groups generally used for or-
ganometallic catalysis, our design incorporates a polyethyle-
neoxy spacer, which can act as the distal regulation site
when folded in the right conformation. We envisaged that
the binding of cationic species (effectors) by the polyethyle-
neoxy moieties through ion-dipole interactions would not
only serve to bring the two terminal ligating groups for the
catalytic metal center close together (template effect;
Figure 1), but also to modify the geometry and flexibility of
the associated catalytic site (adaptive effect of the catalyst;
Figure 1). Changes in geometry and conformational flexibili-
ty provoked by the secondary binding site around the cata-
lytic metal center should modify the catalytic properties and
constitute the basis of our proposed regulation mechanism.
[a] I. Mon, Dr. D. A. Jose, Prof. A. Vidal-Ferran
Institute of Chemical Research of Catalonia (ICIQ)
Avgda. Paꢁsos Catalans 16, 43007 Tarragona (Spain)
Fax : (+34)977920228
E-mail: avidal@iciq.es
[b] Prof. A. Vidal-Ferran
Catalan Institution for Research and Advanced Studies (ICREA)
Passeig Lluꢂs Companys 23, 08010 Barcelona (Spain)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203677.
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FULL PAPER
Scheme 1. Synthesis of a,w-bis(phosphite)–polyethyleneoxy ligands 1a
and 1b.
NEt3 as a base (4.4 equiv) in toluene (Scheme 1). Com-
pounds 1a and 1b were isolated as solids in 83 and 86%
yield, respectively, and then characterized by standard ana-
lytic methods (NMR spectroscopy and HRMS analysis).
Figure 1. Supramolecular bis(phosphite) ligands with distal regulation.
The transformation of alkenes to aldehydes by hydrofor-
mylation constitutes a pivotal industrial process, which re-
quires transition-metal-derived catalysts.[9] Given that chiral
bis(phosphites) have performed well in this important car-
bonylation reaction,[10] we envisaged that the rhodium cata-
lysts derived from our a,w-bis(phosphite)–polyethyleneoxy
ligands 1 would offer the advantage of easy preparation and
the possibility of geometric adaptation to the requirements
of a given substrate for high enantioselectivity, through
distal regulation.
Hydroformylation studies with E@2a and E@2b as cata-
lysts: At the onset of our studies, we were interested in de-
termining in our ligand design the optimal phosphite frag-
ment for highly efficient asymmetric hydroformylations. Fur-
thermore, we also decided to evaluate our design princi-
ple—namely, whether the addition of an effector (alkali
cation) in the hydroformylation reaction medium would
affect the catalytic activity of the rhodium complexes de-
rived from ligands 1. At this point, we considered the use of
a metal alkali cation such as potassium. Cyclic and acyclic
polyethyleneoxy derivatives are well-known receptors for
positively charged species.[11,14] Regarding the different po-
Results and Discussion
tassium sources, K[BACTHNUGTREN(NUG 3,5-ACTHUGNNERTN(UGN CF3)2C6H3)4] (hereafter, KBArF),
was an attractive option, given its solubility in solvents that
are suitable for hydroformylations (e.g, toluene containing a
small amount of THF). We did our initial hydroformylation
studies on vinyl acetate (4a) by using rhodium complexes
derived from the bis(phosphites) 1a and 1b under standard
catalytic conditions (1.0 mol% of precatalyst formed in situ
Ligand synthesis: Our ligand design for the hydroformyla-
tion combines a [1,1’-biphenyl]-2,2’-bisACTHNUTRGENUG(N olate) core (Figure 1,
red fragment) with two polyethyleneoxy units (Figure 1,
blue fragment) as the polyether backbone. We chose a
length of three units for the polyethyleneoxy chain because,
based on literature precedents and previous binding studies
that we had done on analogous receptors, this value ap-
peared to be suitable for strong binding with positively
charged species (i.e., alkali cations).[11] To investigate the op-
timal phosphite fragment in bis(phosphites) 1, we incorpo-
rated into our ligand the phosphite fragment derived
from
[Rh(k2O,O’-acac)(CO)2]
(1 mol%),
ligand
1
(1.2 mol%), and a slight excess of KBArF as effector
(1.56 mol%) under CO/H2 (1:1, 10 bar) in toluene and THF
(97:3 v/v), at 408C, overnight). Although the best results
(Table 1, entry 1) were obtained with ligand 1a, which has
trimethylsilyl substituents at the 3 and 3’ positions of the
1,1’-biaryl moiety, low levels of enantioselectivity were also
observed in the absence of the potassium cation that was
used as an effector (see Scheme 2 and Table 1).
The efficiency of ligands 1a and 1b in the hydroformyla-
tion of 4a was enhanced when KBArF (1.3 equiv relative to
the ligand) was used during the in situ preparation of the
hydroformylation catalysts. The use of this effector salt re-
markably improved the enantioselectivity in the asymmetric
hydroformylation of vinyl acetate (see entries 1 and 2 in
Table 1). Thus, a,w-bis(phosphite)–polyethyleneoxy ligand
from
3,3’-bis(trimethylsilyl)-[1,1’-binaphthalene]-2,2’-diol
(Figure 1, green fragment a), which is considered to be a
privileged module in ligands for asymmetric hydroformyla-
tion.[12] To facilitate a comparison, we also included in our
studies a ligand incorporating a phosphite group derived
3,3’-unsubstituted [1,1’-biaryl]-2,2’-diol moiety
(Figure 1, green fragment b).
a,w-Bis(phosphite)–polyethyleneoxy ligands 1a and 1b
were readily synthesized from the corresponding diol[13] 3 by
treatment with the required chlorophosphite (2.2 equiv) and
from
a
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A. Vidal-Ferran et al.
Table 1. Initial studies on the hydroformylation of 4a by using rhodium
complexes derived from 1a and b with KBArF as an effector.[a]
in the ee for 4e (Table 2, entry 5) to 62% ee for 4a (Table 2,
entry 1).The use of K+ led to regulation effects lower than
those observed for Cs+, with the exception of the allosteric
effects on substrate 4e, which were comparable (see Table 2,
entry 5). In terms of the activity of Cs+@2a as catalyst, the
results summarized in Table 2 reflect the excellent catalytic
performance of this rhodium complex towards vinyl esters.
Generally, regardless of the nature of the ester group (ace-
tate for 4a, propionate for 4b, and benzoate for 4c), the cor-
responding alkenes were efficiently hydroformylated with
full conversion and high enantioselectivities (71 to 90% ee
under catalytic screening conditions; see Table 2, column
E=CsBArF, entries 1–3). On the other hand, with styrene
(4d) and the allyl alcohol derivative 4e, Cs+@2a gave only
mediocre enantioselectivities (20 and 23% ee, respectively;
Table 2, entries 4 and 5). Although a positive regulation
effect was also observed for these two substrates (5% in-
crease in the ee for 4d [Table 2, entry 4]; and 16% increase
in the ee for 4e [Table 2, entry 5]), the strength of the distal
regulation mechanism appears unable to provoke sufficient
adaptive change to the catalyst to enable hydroformylation
with higher enantioselectivity.
Ligand E=none
E=KBArF
Conv. b/l ratio[c] ee [%]
Conv. b/l ratio[c] ee [%]
[%][b]
(config.)[d] [%][b]
ACHTUNGTRENNUNG
1
2
1a
1b
76
69
98.7:1.3
94.4:5.6
28 (S)
17 (S)
66
99
>99:1
[a] Hydroformylations were done in a HEL parallel reactor. Reaction
conditions are indicated in Scheme 2, unless otherwise stated; S/C=
100:1, [S]=0.26m, T=408C, reaction time was 5 h. The values shown are
the average values of at least two independent runs. [b] Conversion, as
determined by GC analysis (b-DexTM 225) with n-dodecane as the inter-
nal standard. [c] Branched (5) to linear (6) product ratio, as determined
by GC analysis (b-DexTM 225, ratio of areas), unless otherwise stated.
[d] Enantioselectivity, as determined by GC with chiral stationary phases.
Absolute configuration was assigned by comparison of the elution order
in GC analysis with the reported data (see the Supporting Information
for details).
Conversion curves for 4a, whose branched hydroformylat-
ed product 5a experienced the highest positive allosteric
effect, were recorded from the gas-uptake profiles (see
Figure 2 and the Supporting Information for details), and
Scheme 2. Asymmetric hydroformylation mediated by E@2.
1a was selected as the lead ligand for subsequent hydrofor-
mylation studies.
Next, we studied the effect produced by different alkali
metal cations on the catalytic activity displayed by the rho-
dium complexes derived from ligand 1a. The asymmetric
hydroformylations of diversely substituted alkene substrates,
comprising vinyl esters (4a–c), styrene (4d), and one deriva-
tive of an allylic alcohol (4e), were used as test reactions.
Although the use of Na+ did not provoke any clear trend in
the activity of the catalytic systems involving 1a (compare
columns E=NaBArF or E=KBArF with column E=none
for all entries, Table 2), the use of Cs+ gave enhanced enan-
tioselectivity for all substrates, ranging from a 16% increase
Figure 2. Conversion plotted against time for the enantioselective hydro-
formylation of 4a catalyzed by rhodium complexes of bis(phosphite)
ligand 1a with (red curve, TOF1/2 =27 hÀ1) and without (black curve,
TOF1/2 =12 hÀ1) Cs+, which is used as an effector.
Table 2. Catalytic studies on the hydroformylation of 4a–e using rhodium complexes derived from 1a and several effectors.[a]
Alkene E=none
E=NaBArF
E=KBArF
E=CsBArF
Conv. b/l ratio[c]
ee [%]
A
Conv. b/l ratio[c]
ee [%]
A
Conv. b/l ratio[c]
ee [%]
A
Conv. b/l ratio[c]
ee [%]
ACHTUNGTRENNUNG
(config.)[d]
[%][b]
(config.)[d] [%][b]
(config.)[d] [%][b]
(config.)[d] [%][b]
1
2
3
4
5
4a
4b
4c
4d
4e
76
>99
>99
>99
98.7:1.3
98.3:1.7
>99:1
28 (S)
27 (S)
9 (S)
15 (S)
7 (S)
57
>99
86
>99:1
>99:1
>99:1
92.3:7.7
23 (S)
24 (S)
9 (S)
66
>99
88
>99:1
>99:1
>99:1
94.7:5.3
64 (S)[e]
58 (S)
32 (S)
0 (-)
95
>99
>99
>99
>99[f]
>99:1
>99:1
>99:1
90 (S)
88 (S)
71 (S)
20 (S)
94.4:5.6
>99
8 (S)
>99
94.1:5.9
>99[f] 56.5:43.5[f]
>99[f] 66.7:33.3[f] 24 (S)
>99[f] 58.3:41.7[f] 24 (S)
52.6:47.4[f] 23 (S)
ACHTUNGTRENNUNG[a,b,c,d] See Table 1 for details and Scheme 2 for reaction conditions and structures. Reaction time for 4a was 5 h, and for 4b–e was 18 h. The values
shown are the average values of at least two independent runs. [e] Although these results were already presented in Table 1, they have been included in
1
this table to aid comparison. [f] Conversion and b/l product ratio were determined by H NMR analysis.
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Bis(phosphite) Ligands with Distal Regulation
FULL PAPER
then used to calculate turnover frequency (TOF) values at
approximately 50% conversion (TOF1/2). Interestingly, the
TOF value was higher when Cs+ was used (TOF1/2 =27 hÀ1
for Cs+@2a, 408C, substrate/catalyst (S/C)=100:1; TOF1/2
12 hÀ1 for 2a under the same conditions).
=
This observation clearly indicates that Cs+ also induces a
positive allosteric effect in the reaction rate of 4a. Hydrofor-
mylations aimed at measuring gas uptake were done at a
higher scale (ca. three times as much 4a was used as in the
screening experiments) in an automated autoclave, with all
other reaction conditions maintained (see footnote [a] in
Table 1 for details). To our satisfaction, the enantioselectivi-
ty was further enhanced to 92% ee. To the best of our
knowledge, our result with Cs+@2a represents the highest
enantioselectivity ever reported for hydroformylation of
vinyl acetate using a bis(phosphite)-type ligand (92% ee)
and is close to the highest value ever reported for chiral
phosphorus ligands (97% ee).[9]
Binding studies: To elucidate the structure of the catalytic
species involved in this chemistry, we performed complexa-
tion experiments between the rhodium-precursor that was
used ([Rh(k2O,O’-acac)(CO)2]), the ligand 1a, and the best
regulator (Cs+; see Figure 3). The association of 1a with
CsBArF in the solvent mixture used for hydroformylations
(toluene/THF, 97:3 v/v) was studied by NMR spectrosco-
py.[15] 1H NMR analysis qualitatively demonstrated the bind-
ing of Cs+ within the polyethyleneoxy moieties: the addition
of incremental amounts of the metal salt to a solution of 1a
caused significant changes to the chemical shift, multiplicity,
and signal width of the polyethyleneoxy fragments. In
31P{1H} NMR analysis, the phosphite signal shifted downfield
(ca. 0.8 ppm) upon the addition of a solution of CsBArF to
a solution of 1a (Figure 3b). The association constant was
calculated from the NMR titration data by nonlinear curve
fitting,[16] assuming a 1:1 binding model, and was found to
be K=4.4ꢄ103 mÀ1 at 258C in a mixture of [D8]toluene and
[D8]THF (97:3 v/v).
The addition of equimolar amounts of [Rh(k2O,O’-
acac)(CO)2] to a solution of 1a (ca. 10 mm, see Figure 3c)
ACTHNUTRGNEUNG
led to the formation of [Rh(k2O,O’-acac)(CO)( k1P-1a)] as
the only detected species in solution by displacement of one
of the CO groups by one phosphite-binding group. The pres-
ence of one carbonyl group was confirmed by IR studies
(CO stretching vibration at 2010 cmÀ1)[17] and the monoden-
tate nature of 1a in the complex was confirmed by
31P{1H} NMR spectroscopy (Figure 3c), which revealed a
Figure 3. Complexation studies between [Rh(k2O,O’-acac)(CO)2], 1a,
and CsBArF.
doublet centered at d=138.4 ppm (1JRh P =297 Hz) and a
À
singlet at d=137.5 ppm, which were assigned to the bound
and
unbound
phosphite
groups,
respectively.
the solution with a CO/H2 mixture (1:1, overall 10 bar; Fig-
ure 3d), thus indicating that the presence of CO/H2 did not
affect the coordination mode of the a,w-bis(phosphite)–pol-
yethyleneoxy ligand 1a. The absence of chelated rhodium
complexes derived from 1a (Figure 3d) could account for
the low enantioselectivities observed when rhodium com-
plexes of this ligand were used in asymmetric hydroformyla-
tions (Table 2, column E=none).
31P{1H} exchange spectroscopy (EXSY) experiments re-
vealed chemical exchange between the Rh-coordinated
phosphite group (doublet marked in blue in Figure 3c) and
the unbound one. Analogous rhodium complexes have been
obtained from other bis(phosphite) ligands and [Rh(k2O,O’-
acac)(CO)2] under similar conditions.[18] Very minor changes
were observed in the 31P NMR spectra[19] upon pressurizing
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A. Vidal-Ferran et al.
400 MHz spectrometer. 1H NMR and 13C NMR chemical shifts were
quoted in ppm relative to residual solvent peaks, whereas 31P{1H} NMR
chemical shifts were quoted in ppm relative to 85% phosphoric acid in
water. IR spectra were recorded using Attenuated Total Reflection
(ATR). Mass spectra were obtained by electrospray ionization (ESI,
HRMS). Melting points were determined in open capillaries and are un-
corrected.
The presence of a slight excess of CsBArF in the previous
sample (1.3 equiv relative to 1a) translated to a change in
the coordination mode of ligand 1a (Figure 3e). Here,
unlike in the absence of polyethyleneoxy binder, 1a showed
a bidentate coordination mode, which was confirmed by
31P NMR analysis based on the presence of a doublet at d=
150.0 ppm (1JRh P =247 Hz) in the spectrum. MS and
Preparation of ligand 1a: Under an atmosphere of argon, (R)-3,3’-bis(tri-
methylsilyl)-[1,1’-binaphthalene]-2,2’-diol (666 mg, 1.55 mmol) was azeo-
tropically dried with toluene (3ꢄ1 mL). The remaining solid was dis-
solved in anhydrous toluene (20 mL) and slowly added to a stirred solu-
tion of PCl3 (170 mL, 1.95 mmol) and NEt3 (0.61 mL, 4.4 mmol) in dry
toluene (20 mL) at 08C. The solution was allowed to reach room temper-
ature and was stirred overnight. The turbid reaction mixture was filtered
and the solvent evaporated under reduced pressure. The resulting residue
was dissolved in dry toluene (20 mL) and NEt3 (0.61 mL, 4.4 mmol). A
solution of diol 3 (316 mg, 0.71 mmol, in 20 mL of toluene) was slowly
added to the first solution and allowed to react overnight at room tem-
perature. The reaction mixture was filtered and the solvent evaporated
under reduced pressure. The resulting crude mixture was purified by
column chromatography on silica gel C18 by using acetonitrile/ethyl ace-
tate (1:1) as the elution solvent to provide 1a as a white solid (840 mg,
86% yield). M.p. 145–1638C; [a]2D5 =À563.8, (c=0.12 in toluene);
1H NMR (400 MHz, [D2]CH2Cl2): d=8.14–8.07 (m, 4H), 7.96–7.88 (m,
4H), 7.43–7.36 (m, 4H), 7.25–7.11 (m, 10H), 7.09–7.03 (m, 2H), 6.94–
6.84 (m, 4H), 4.01–3.97 (m, 4H), 3.96–3.88 (m, 2H), 3.61–3.53 (m, 4H),
À
13C NMR studies excluded the formation of oligomers under
these conditions.[20] Hydride formation was observed in the
1H NMR spectrum, which exhibited a broad signal centered
1
at d=À10.5 ppm. Unfortunately, the JRh and 2JPÀ cou-
À
H
H
pling constants were small and led to signal broadening
rather than proper signal splitting (width of the hydride
signal at half heightꢀ9 Hz; Figure 3e). Thus, the P–H cou-
pling was demonstrated by 1H–31P HMBC spectroscopy,
which showed a crosspeak between the hydrido and the
phosphite groups. Such small Rh–H and P–H couplings are
indicative that the hydride has a strong preference for cis
disposition relative to the P atoms, which are coordinated in
an equatorial–equatorial fashion to a trigonal-bipyramidal
rhodium center (Figure 3e).[21] Other Rh complexes with
this type of spatial disposition of hydrido and carbonyl li-
gands have performed well as catalysts for asymmetric hy-
droformylations.[21b]
ACTHNUTRGNEUNG
3.43–3.33 (m, 12H), 0.46 (s, 18H), 0.45 ppm (s, 18H); 13C{1H,31P} NMR
(125 MHz, [D2]CH2Cl2): d=156.7, 153.0, 152.2, 137.6, 137.5, 134.3, 134.2,
133.0, 132.3, 132.0, 131.4, 131.0, 128.82, 128.79, 128.76, 128.5, 127.0, 126.9,
126.8, 125.19, 125.16, 123.0, 122.2, 120.8, 112.7, 71.0, 70.9, 70.8, 70.0, 68.7,
64.2, 0.1, 0.0 ppm; 31P{1H} NMR (202 MHz, [D2]CH2Cl2): d=138.7 ppm;
IR (neat): n˜ =3050, 2950, 2894, 2872, 1617, 1576, 1481, 1439, 1383, 1301,
Conclusion
1221, 975, 947, 828, 745 cmÀ1
;
HRMS (ESI): m/z calcd for
C76H88O12P2Si4 +Na+: 1389.4726 [M+Na]+; found: 1389.4757.
We have reported here an efficient synthesis of a,w-bi-
s(phosphite)–polyethyleneoxy ligands 1a and 1b for asym-
metric hydroformylations. Complexation studies between
General procedure for the Rh-catalysed asymmetric hydroformylation:
In a glovebox filled with nitrogen, solutions of ligand 1a or 1b (2.7 mmol
in 360 mL of toluene), E (3.6 mmol in 27 mL of THF), and [Rh(k2O,O’-
acac)(CO)2] (2.3 mmol in 65 mL of toluene) were placed into a 2 mL vial
equipped with a magnetic bar. Substrate (230 mmol), dodecane (69 mmol),
and additional toluene (450 mL) were added to provide the desired final
reaction mixture in toluene/THF (97:3 v/v). The vial was transferred into
an autoclave and taken out of the glovebox. The autoclave was purged
three times with syngas (H2/CO 1:1 at a pressure not higher than 10 bar)
and then pressurized with syngas to the desired pressure. The reaction
mixture was stirred at 408C (oil bath) for 18 h. The reaction mixture was
cooled and the pressure was carefully released in a well-ventilated hood.
The conversion, branch/linear ratio, and enantiomeric excesses for the
hydroformylation products of 4a–d were determined by GC analysis with
a Supelcoꢀs Beta Dex 225 column by using dodecane as an internal pat-
tern from the crude reaction mixture. Conversion and the branch/linear
ratio for the hydroformylation product of 4e were determined by
1H NMR analysis of the crude reaction mixture (see the Supporting In-
formation for details).
these ligands,
a
rhodium precursor ([Rh(k2O,O’-
acac)(CO)2]), and an alkali metal salt (E=CsBArF) have
demonstrated that [Rh]/1/E (1:1:1) chelates that are suitable
chiral (pre)catalysts for the aforementioned reaction are
formed. We have proven that small amounts of polyethyle-
neoxy binders regulate the activity of the enantioselective
hydroformylation catalysts by biasing the distribution of
enantiomers, as evidenced by an increase in enantioselectivi-
ty of up to 62% ee. The presence of cesium salts improved
the chiral hydroformylation catalysts derived from bis(phos-
phite) 1a, offering enhanced enantioselectivities for an array
of diversely substituted substrates (Cs+ for 4a–d, and K+ or
Cs+ for 4e). We are currently tackling the design of new
asymmetric catalysts with distal regulation mechanisms for
hydroformylation, hydrogenation, and other pivotal enantio-
selective transformations.
Acknowledgements
We thank MICINN (Grant CTQ2011–28512), DURSI (Grant
2009SGR623), and the ICIQ Foundation for financial support. A.J. grate-
fully acknowledges the Marie Curie Incoming Program for financial sup-
port (Grant PIIF-GA-2008–219537) and I.M. thanks the ICIQ Founda-
tion for a predoctoral fellowship.
Experimental Section
General methods: All syntheses were carried out using chemicals as pur-
chased from commercial sources unless otherwise cited. All manipula-
tions and reactions were performed under an inert atmosphere. Glass-
ware was dried in vacuo before drying with a hot air gun. All solvents
were dried and deoxygenated by using a Solvent Purification System
(SPS). Silica gel 60 (230–400 mesh) or Silica-C18 was used for column
chromatography. NMR spectra were recorded in [D2]CH2Cl2 with a
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Chem. Eur. J. 2013, 19, 2720 – 2725

Bis(phosphite) Ligands with Distal Regulation
FULL PAPER
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constant due to the lower temperature (08C instead of 258C) and
the effects of the CO/H2 atmosphere were observed [d=138.4 ppm
1
(doublet, JRh P =293 Hz) and d=136.4 ppm (singlet)].
À
[20] The 13C NMR spectrum of the mixture shown in Figure 3e indicates
the presence of one species. The formation of a rhodium chelate
with a well-defined stereochemistry is demonstrated by MS (m/z
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Received: October 15, 2012
Revised: November 29, 2012
Published online: January 10, 2013
Chem. Eur. J. 2013, 19, 2720 – 2725
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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