Asymmetric Hydroformylation of Heterocyclic Olefins Mediated by Supramolecularly Regulated Rhodium-Bisphosphite Complexes

Article abstract of DOI:10.1021/acs.joc.5b01805

Rhodium complexes derived from conformationally transformable α,ω-bisphosphite ligands combined with a suitable alkali metal BArF salt as a regulation agent (RA) provide high regio- and enantioselectivities in the asymmetric hydroformylation (AHF) of three heterocyclic olefins. The outcome of the AHF could be exquisitely regulated by choosing the appropriate RA with an increase in the ee, the reversal of the regioselectivity, or the complete suppression of one byproduct.

Full text of DOI:10.1021/acs.joc.5b01805

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Note
Asymmetric Hydroformylation of Heterocyclic Olefins Mediated by
Supramolecularly Regulated Rhodium-Bisphosphite Complexes
Laura Rovira, Mónica Vaquero, and Anton Vidal-Ferran
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01805 • Publication Date (Web): 10 Sep 2015
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Asymmetric Hydroformylation of Heterocyclic Olefins
Mediated by Supramolecularly Regulated Rhodiumꢀ
Bisphosphite Complexes
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Laura Rovira†, Mónica Vaquero† and Anton VidalꢀFerran †‡*
†Institute of Chemical Research of Catalonia (ICIQ), Avgda. Països Catalans 16, 43007
Tarragona, Spain. Phone +34 977920210, Fax + 34 977920228.
‡Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluís Companys 23,
08010 Barcelona, Spain.
*Corresponding author: Eꢀmail. avidal@iciq.cat
Received Date (will be automatically inserted after manuscript is accepted)
Table of Contents/abstract graphic.
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Abstract: Rhodium complexes derived from conformationally transformable α,ωꢀbisphosphite
ligands combined with a suitable alkali metal BArF salt as regulation agent (RA) provide high
regioꢀ and enantioselectivities in the asymmetric hydroformylation (AHF) of three heterocyclic
olefins. The outcome of the AHF could be exquisitely regulated by choosing the appropriate RA
with an increase in the ee, the reversal of the regioselectivity or the complete suppression of one
byproduct.
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The development of efficient strategies for generating libraries of enantioselective catalysts with
minimal synthetic efforts remains an appealing challenge. Supramolecular interactions have
been used to regulate the size, shape and first coordination sphere of a chiral catalyst.1 However,
there are few examples of the fine modification of the geometry of the active site.2,3 Our group
has developed supramolecularly regulated bisphosphite ligands possessing two different
structural features: a catalytic site consisting of two identical phosphite fragments and a distal
regulation site containing a polyether chain. Ionꢀdipole interactions between the polyether chain
and the regulation agent (RA; e.g. alkali metal salts; see Scheme 1) bring the ligating groups
together at the metal center.2 Furthermore, the library of catalysts arising upon the binding of an
array of RAs to the regulation site preserve most of the structural characteristics but also
incorporate structural peculiarities that depend on the size and shape of the RA employed.
Hydroformylation is an attractive industrial process requiring transition metal catalysts,4 from
which rhodium complexes derived from bisphosphite ligands have been used with variable
success in the hydroformylation of heterocyclic alkenes.5 Herein we describe the design and
synthesis of new supramolecularly regulated ligands (R,S)ꢀL2 and (S,S)ꢀL3 (Scheme 1), which
incorporate a [1,1'ꢀbinaphthalene]ꢀ2,2'ꢀdiol motif in the regulation site. We also show that the
inclusion of this motif reinforces the regulation ability of the catalysts and leads to efficient
AHF catalysts for a number of heterocyclic olefins.
The new ligands (R,S)ꢀL2 and (S,S)ꢀL3 were synthesized by Oꢀphosphorylation6 of the
corresponding diol derivatives. Ligand (S)ꢀL1, which lacks a stereogenic element in the
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regulation site, was also considered in order to aid comparison and was synthesized in an
analogous manner (see the experimental section).
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We first tested the activity of these new ligands in the AHF of benchmark substrates comprising
vinyl esters 1a−c, styrene 1d and (allyloxy)trimethylsilane 1e (Scheme 2; Table 1). Initial
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studies were performed with [Rh(κ2O,O´ꢀacac)(CO)2] and the corresponding ligand at 40 °C
under 10 bar syngas in toluene, with the minimum amount of THF to solubilize the RA.2a,c The
results on AHF are partially summarized in Table 1, which summarizes the results for the
catalysts that show the highest positive regulation effects.7 In the case of vinyl ester derivatives
1a−c, the reactions performed in the absence of RAs yielded aldehydes with lower conversions
than those in which an RA was used. Rhodium complexes derived from ligands (S)ꢀL1 and
(R,S)ꢀL2 provided highly active catalysts and remarkable enhancements in the enantioselectivity
of the hydroformylation of 1a−c (with increases ranging from 69 to 77% ee; see entries 1−6 in
Table 1). The combined use of (S,S)ꢀL3 and NaBArF provided the highest enantioselectivity for
styrene (b/l ratio = 96:4; 54% ee; see entry 8 in Table 1), while the highest enantioselectivities
were achieved for compound 1e with (S,S)ꢀL3 and CsBArF (b/l ratio = 18:82; 23% ee; see entry
10 in Table 1). The principal steric directors in our catalysts are the bisphosphite units, which
favor the formation of (R)ꢀconfigured products, although the configuration of the [1,1'ꢀ
binaphthalene]ꢀ2,2'ꢀdiol motif is also decisive in obtaining the highest performing ligands.
After testing the AHF of linear substrates with our catalysts, we moved on to the AHF of
heterocyclic olefins, given the applicability of enantiopure heterocyclic aldehydes in the
synthesis of biologically relevant products.8 Our group9 and others have studied the AHF of
fiveꢀ,5b,8a,10 sixꢀ10d and sevenꢀ5b,10a,10c membered heterocyclic olefins and reported problems in
the control of chemoꢀ and regioselectivity.
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Scheme 1. Supramolecularly regulated bisphosphite ligands with a distal regulation site.
Scheme 2. AHF of compounds 1a−e mediated by supramolecularly regulated ligands L1−3.
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Table 1. AHF of 1a−e using the catalysts leading to the highest regulation effectsa
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6
7
8
entry
ligand
substrate
RA
conv (%) b:l ratio
ee of 2 (%) config.
23 (R)
1
2
(R,S)ꢀL2
ꢀ
92
>99
94
>99:1
>99:1
>99:1
>99:1
>99:1
98:2
1a
9
RbBArF
92 (R)
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3
(R,S)ꢀL2
(S)ꢀL1
ꢀ
15 (R)
1b
1c
1d
1e
4
KBArF
>99
90
92 (R)
5
ꢀ
7 (S)
6
NaBArF
ꢀ
78
76 (R)
7
(S,S)ꢀL3
(S,S)ꢀL3
>99
>99
>99b
>99b
95:5
42 (R)
8
NaBArF
ꢀ
96:4
54 (R)
9
61:39b
18:82b
17 (R)
10
CsBArF
23 (R)
a
Reaction conditions are shown in Scheme 2. Conversion was determined by GC
chromatography (β−DexTM 225) using nꢀdodecane as internal standard unless otherwise
stated. The ratio of the regioisomers and ee values were determined by GC analysis on a
chiral stationary phase (β−DexTM 225) unless otherwise stated. Absolute configurations
were assigned by comparing the elution order in GC analysis with reported data (for details
see Experimental Section). b Conversion and regioselectivity were determined by 1H NMR.
In the AHF of 2,5ꢀdihydrofuran, the expected tetrahydrofuranꢀ3ꢀcarbaldehyde (6), the
regioisomeric aldehyde 5 and 2,3ꢀdihydrofuran (7) can be formed (Scheme 3; Table 2). The
latter compound arises from a C=C bond isomerization that occurs simultaneously with the
hydroformylation.11
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Scheme 3. AHF of 4 and 7 mediated by supramolecularly regulated ligands L1−3.
The supramolecularly regulated ligands L1−3 proved to be very active in the AHF of 2,5ꢀ
dihydrofuran (with conversions ranging from 92 to >99%; Table 2). In the reactions performed
without an RA, carbaldehyde 6 was obtained as the major product, although in poor
enantioselectivities (from 36 to 38% ee; Table 2), together with small amounts of isomerization
product 7 (from 5 to 9%; see entries 1, 6 and 11; Table 2). The combined use of (R,S)ꢀL2 with
KBArF as the RA had several major effects in the outcome of the reaction. First, the use of
ligand (R,S)ꢀL2 and KBArF brought about a reversal of regioselectivity in favor of
tetrahydrofuranꢀ2ꢀcarbaldehyde (5/6 ratio from 1:92 to 35:39; compare entries 6 and 8 in Table
2), and second, they induced a change in the configuration of the final product and an increase
in the ee (from 11% ee in favor of (S)ꢀ5 to 82% ee in favor of (R)ꢀ5; compare entries 6 and 8 in
Table 2). It is interesting that the reversal of regioselectivity was associated with major amounts
of isomerization product 7 (from 7 to 26%; compare entries 6 and 8 in Table 2).
To gain more information about this complex transformation, the hydroformylation of 2,3ꢀ
dihydrofuran under the same conditions was also studied (see Scheme 3 and Table 3). Substrate
7 reacted more slowly than compound 4 under the same reaction conditions, with or without an
RA (conversion from 7 to 89%; Table 3). The use of an RA increased activity in almost all the
examples tested. The major product of the hydroformylation of 7 was tetrahydrofuranꢀ2ꢀ
carbaldehyde (5) in moderate to high enantioselectivities (e.g., (R,S)ꢀL2 and KBArF led to 81%
ee in favor of (R)ꢀ5; entry 8 in Table 3).
So as to minimize the formation of isomerization product 7 and enhance regioselectivity toward
carbaldehyde 5, we decided to study the effect of variable amounts of H2 and CO in the syngas
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mixture on the outcome of the AHF of 4. We also hoped to be able to identify the AHF
conditions leading to carbaldehyde 5 being the most abundant product. These studies were
performed with ligand (R,S)ꢀL2 and KBArF, as their combined use provided the best results in
terms of enantioselectivity for product 5 (see entry 8 in Table 2).
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Table 2. AHF of 4 using Rhꢀcomplexes of ligands L1−3 and a set of BArF salts as RAsa
conv
(%)
>99
92
ratio
entry
ligand
RA
ee of 5 (%) config. ee of 6 (%) config.
5:6:7
1
2
(S)ꢀL1
ꢀ
2:93:5
23 (S)
60 (R)
74 (R)
77 (R)
52 (R)
11 (S)
2 (S)
38 (R)
61 (S)
60 (S)
21 (S)
15 (R)
36 (R)
25 (R)
56 (S)
52 (S)
14 (S)
38 (R)
42 (R)
2 (S)
NaBArF
KBArF
RbBArF
CsBArF
ꢀ
5:73:22
21:15:64
25:31:44
13:72:15
1:92:7
3
>99
>99
>99
>99
98
4
5
6
(R,S)ꢀL2
7
NaBArF
KBArF
RbBArF
CsBArF
ꢀ
1:91:8
8
>99
>99
>99
98
35:39:26
34:26:40
19:38:43
1:90:9
82 (R)
81 (R)
76 (R)
10 (S)
34 (S)
18 (R)
45 (R)
43 (R)
9
10
11
12
13
14
15
(S,S)ꢀL3
NaBArF
KBArF
RbBArF
CsBArF
>99
96
1:97:2
3:85:12
4:69:27
5:70:25
93
13 (S)
18 (R)
97
a See footnote a in Table 1 for details, with the following remarks: Reaction conditions are shown
in Scheme 3 and the amount of 7 was determined by 1H NMR.
The AHF of 4 at 10 bar employing a 1:1 H2/CO mixture led to 5 in a selectivity of 35% with
82% ee, together with the formation of 7 with a selectivity of 26%. Independently of the total
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pressure employed in the AHF, increasing the amount of H2 with respect to CO led to an
increase in selectivity toward 5 and a reduction in the amount of isomerization product 7 (see
Table SI 6 and Figure SI 1 in the Supporting Information).12 One of the most attractive AHF
conditions was obtained at 5 bar with a 4:1 H2/CO mixture, under which 7 was not detected and
carbaldehyde 5 was formed with a selectivity of 71% with 69% ee (Figure 1).
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Ligands L1−3 were also tested in the AHF of sixꢀmembered heterocyclic olefins (see SI for the
substrates studied and results obtained). Unfortunately our catalysts were not active in the AHF
of these types of compounds. It has already been reported in the literature that these substrates
normally require harsh reaction conditions in AHF, which reduce control of regioꢀ and
enantioselectivity.11
Figure 1. AHF of 4 at 5 bar with different syngas mixtures.
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Table 3. AHF of 7 using Rhꢀcomplexes of ligands L1−3 and a set of BArF salts as RAsa
5
6
7
8
conv
(%)
7
ratio
entry
ligand
RA
ee of 5 (%) config. ee of 6 (%) config.
5:6:7
9
1
2
(
S
)ꢀL1
ꢀ
2:5:93
5 (
S
)
26 (
44 (
S)
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NaBArF
KBArF
RbBArF
CsBArF
ꢀ
31
23
39
89
32
40
65
57
40
29
31
50
32
28
18:13:69
21:2:77
34:5:61
57:32:11
12:20:68
17:23:60
52:13:35
48:9:43
33:7:60
10:19:71
11:20:69
30:20:50
22:10:68
19:9:72
62 (
76 (
79 (
56 (
R
R
R
R
)
R)
3
)
)
)
)
8 (
2 (
6 (
S
)
)
)
4
S
S
5
6
(
R,
S)ꢀL2
13 (
S
16 (S)
7
NaBArF
KBArF
RbBArF
CsBArF
ꢀ
3 (
S)
8 (R)
8
81 (
79 (
75 (
R
R
R
)
20 (
10 (
R
)
)
9
)
)
)
R
10
11
12
13
14
15
rac
(
S
,S)ꢀL3
11 (
S
14 (
15 (
S
)
)
NaBArF
KBArF
RbBArF
CsBArF
24 (
S)
S
19 (
44 (
44 (
R
R
R
)
)
)
rac
13 (
16 (
S
)
S
)
a See footnote a in Table 1 for details, with the following remarks: Reaction conditions are shown
in Scheme 3 and the amount of 7 was determined by 1H NMR.
Finally, ligands (
S)ꢀL1, (R,S)ꢀL2 and (S,S)ꢀL3 were tested in the AHF of cisꢀ4,7ꢀdihydroꢀ1,3ꢀ
dioxepin (8) with a set of alkali BArF salts as RAs (see Scheme 4 and Table 4).
Scheme 4. AHF of 8 mediated by supramolecularly regulated ligands L1−3.
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The reactions showed complete regioselectivity toward product 9 (see Table 4 and Table SI 8).
4
5
The use of RAs led to a great improvement in the conversion (up to 82%) and enantioselectivity
6
7
(up to 79%). The highest enantioselectivities were obtained with combinations (
S)ꢀL1/NaBArF
8
(85% ee), ( )ꢀL2/KBArF (83% ee) and (S,S)ꢀL3/RbBArF (74% ee) (entries 2, 5 and 8
R,S
9
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respectively; Table 4). In order to increase the enantioselectivity, these reactions were performed
at room temperature (entries 3, 6, and 9 in Table 4). Improvements ranging from 7 to 15% in the
ee were observed, with the combination (R,S)ꢀL2/KBArF being the best for this transformation.
Carbaldehyde 9 was obtained with an excellent enantioselectivity (93% ee), which to the best of
our knowledge is the highest reported for this substrate.10a
Table 4. AHF of 8 using Rhꢀcomplexes of ligands L1−3 and a set of BArF salts as RAsa
entry
ligand
)ꢀL1
RA
ꢀ
conv (%)
28
ee of 9 (%)b
6 (+)
1
2
(
S
NaBArF
NaBArF
ꢀ
>99
95
85 (+)
3c
4
92 (+)
(
R
,S
)ꢀL2
23
10 (−)
5
KBArF
KBArF
ꢀ
>99
>99
17
83 (+)
6c
7
93 (+)
rac
(S,S)ꢀL3
8
RbBArF
>99
74 (+)
89 (+)
9c
RbBArF
93
a
See footnote a in Table 1 for details, with the following remarks: Reaction conditions are
shown in Scheme 4.b Absolute configuration is unknown and the sign of the optical rotation is
provided.c Reaction performed at 25 °C.
To elucidate the structure of the catalytic species, complexation experiments between
[Rh(κ2O,O´ꢀacac)(CO)2], ligand (
R
,S)ꢀL2 and one representative RA (KBArF) were performed.
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These compounds were reacted at 40 °C under 10 bar of 1:1 H2/CO. Interestingly, the expected
4
5
6
hydridoꢀdicarbonyl chelate [Rh(H)(CO)2(κ2P,P´−ΚΒArF·( )ꢀL2)] was efficiently formed.13
R,S
7
8
9
NMR analysis showed the hydrido signal as a broad and partially resolved multiplet centered at
−10.38 ppm (2JPH = 22 Hz). The value of this coupling constant indicates that the system
undergoes an equilibrium between two hydridoꢀdicarbonyl rhodium complexes with the two Pꢀ
ligating groups coordinated in an equatorialꢀequatorial or apicalꢀequatorial fashion to a trigonalꢀ
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bipyramidal rhodium center.14 The complexation behavior of ligand (
of ligand ( )ꢀL1, which lacks the biaryl core in the regulation site. NMR analysis on the
hydridoꢀdicarbonyl chelate derived from ( )ꢀL1 indicated that the two Pꢀligating groups
R,S)ꢀL2 is different to that
S
S
coordinated in an equatorialꢀequatorial fashion14 (see experimental section and SI). This
difference in coordination behavior between ligands containing or not the [1,1'ꢀbinaphthalene]ꢀ
2,2'ꢀdiol motif in the regulation site could account for the higher activity of ligand (
the AHF of heterocyclic alkenes.
R,S)ꢀL2 in
In summary, challenging heterocyclic olefins were efficiently hydroformylated in terms of
regioꢀ and enantioselectivities with supramolecularly regulated rhodium complexes derived
from bisphosphite ligands L1−3. Small amounts of polyetherꢀbinder RAs were shown to
regulate the activity of the AHF catalysts. The distribution of the enantiomers was biased in
some examples (rhodium complexes of a ligand and an RA enabled up to 86% higher
enantioselectivities compared with those obtained in the reactions of the corresponding
complexes without an RA). In the AHF of 2,5ꢀdihydrofuran we have demonstrated the potential
of our supramolecularly regulated catalysts, since the use of an alkali metal BArF salt as RA
increased the enantioselectivity (up to 33% ee), reversed the regioselectivity of the reaction or
completely suppressed the formation of the sideꢀproduct.
EXPERIMENTAL SECTION
General information: All syntheses were carried out using chemicals as purchased from
commercial sources unless otherwise cited. All manipulations and reactions were performed
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under inert atmosphere. Glassware was dried in vacuo before use 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 SilicaꢀC18 (200−400 mesh) were used for column chromatography. NMR
1
spectra were recorded in CDCl3 unless otherwise cited. H NMR and 13C NMR chemical shifts
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were quoted in ppm relative to residual solvent peaks, whereas 31P NMR chemical shifts were
quoted in ppm relative to 85% phosphoric acid in water. IR spectra were recorded using
Attenuated Total Reflection (ATR) technique unless otherwise cited. Highꢀresolution mass
spectra (HRMS) were recorded by using an electrospray ionization (ESI) method in positive
mode for the ligands (L1−3) and diols ((
desorption ionization (MALDI) in positive mode for [Rh(H)(CO)2(κ2P,P’−KBArF·(
[Rh(H)(CO)2(κ2P,P’−KBArF·(
R,S)ꢀL2)], using in all cases a time of flight (TOF) detector.
R)ꢀD2 and (S)ꢀD2) , and matrixꢀassisted laser
S)ꢀL1)] and
Melting points were determined in open capillaries and are uncorrected. Enantiomeric excesses
were determined by GC equipped with a FID detector using chiral stationary phases
.
Synthesis of ligand (S)ꢀL1: (S)ꢀ5,5’ꢀ6,6´ꢀtetramethylꢀ3,3´ꢀdiꢀtbutylꢀ1,1’ꢀbiphenylꢀ2,2’ꢀdiol
(265 mg, 0.75 mmol) was azeotropically dried with toluene (3 x 2 mL), dissolved in anhydrous
toluene (ca. 10 mL) and slowly added to a stirred solution of PCl3 (82.4 ꢀL, 0.94 mmol) and
NEt3 (297 ꢀL, 2.14 mmol) in dry toluene (ca. 10 mL) at 0 °C. The solution was allowed to reach
room temperature and was stirred overnight. The turbid reaction mixture was filtered and the
solvent evaporated under reduced pressure. The resulting residue was dissolved in ca. 10 mL of
dry toluene and NEt3 (297 ꢀL, 2.14 mmol). A solution of the tetraethylenglycol (66.8 mg, 0.34
mmol in ca. 10 mL of toluene) was slowly added to the previous solution and allowed to react
overnight at room temperature. 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 using acetonitrile/EtOAc 1:1 as elution solvent to get the expected
bisphosphite ligand (S
)ꢀL1 as a white solid. Isolated 312 mg, 83% yield. 1H NMR (CDCl3, 500
MHz): δ 7.15 (s, 2H), 7.11 (s, 2H), 3.96−3.91 (m, 2H), 3.60−3.55 (m, 8H), 3.54−3.48 (m, 6H),
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2.25 (s, 6H), 2.24 (s, 6H), 1.85 (s, 6H), 1.78 (s, 6H), 1.45 (s, 18H), 1.42 (s, 18H). 13C{1H} NMR
(CDCl3, 125 MHz): δ 145.5, 145.5, 138.2, 138.2, 137.0, 135.1, 134.5, 132.5, 131.9, 131.8,
131.7, 130.8, 130.8, 128.2, 127.9, 71.0, 70.9, 70.7, 63.6, 63.6, 34.8, 34.8, 31.5, 31.5, 31.3, 20.6,
16.9, 16.7. 31P{1H} NMR (CDCl3, 202 MHz): δ 132.6 (s). HRMSꢀESIꢀTOF (m/z): [M+Na]+
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calcd for C56H80O9P2Na 981.5170; found 981.5191. [ꢀ]ꢂꢁꢃ = +371.8 (
1) ῡ 2963, 2867, 1254, 1027, 870. Mp 71.2−72.6 °C.
c
0.1, DCM). IR (neat, cmꢀ
Synthesis of Ligand (R,S)ꢀL2: A mixture of (R)ꢀ[1,1'ꢀbinaphthalene]ꢀ2,2'ꢀdiol (1.75 g, 6.13
mmol), 2ꢀ(2ꢀhydroxyethoxy)ethyl 4ꢀmethylbenzenesulfonate15 (3.19 g, 12.3 mmol) and K2CO3
(3.64 g, 26.3 mmol) in dry acetonitrile (53 mL) was refluxed for 72 h. The reaction mixture was
filtered and then concentrated under reduced pressure. The crude product was purified by
column chromatography over silica gel (EtOAc/MeOH 95:5 as eluent) to afford the desired
product
(R)ꢀ2,2'ꢀ((([1,1'ꢀbinaphthalene]ꢀ2,2'ꢀdiylbis(oxy))bis(ethaneꢀ2,1ꢀdiyl))bis(oxy))diethaꢀ
nol ((
R
)ꢀD2; see the SI for the spectra) as a clear brown oil. Isolated 1.33 g, 46% yield. 1H NMR
(CDCl3, 500 MHz,): δ 7.95 (d,
2H), 7.35−7.32 (m, 2H), 7.24−7.21 (m, 2H), 7.16 (s, 1H), 7.14 (s, 1H), 4.17−4.13 (m, 2H),
4.03−3.99 (m, 2H), 3.53−3.49 (m, 2H), 3.45−3.38 (m, 6H), 3.22−3.15 (m, 4H), 2.56 (t, = 6.6
J = 9.1 Hz, 2H), 7.87 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 9.1 Hz,
J
Hz, 2H). 13C{1H} NMR (CDCl3, 125 MHz): δ 154.4, 134.2, 129.6, 129.5, 128.0, 126.5, 125.6,
123.9, 120.8, 116.1, 72.5, 70.0, 69.7, 61.7. HRMSꢀESIꢀTOF (m/z): [M+Na]+ calcd for
C28H30NaO6 485.1935; found 485.1923. [ꢀ]ꢂꢁꢃ = +43.1 (
2927, 2869, 1240, 1054. Ligand ( )ꢀL2 was synthesized from (
diꢀ butylꢀ1,1’ꢀbiphenylꢀ2,2’ꢀdiol (424 mg, 1.2 mmol) which was azeotropically dried with
c
0.1, DCM). IR (neat, cmꢀ1) ῡ 3414,
R
,
S
S)ꢀ5,5’ꢀ6,6´ꢀtetramethylꢀ3,3´ꢀ
t
toluene (3 x 2 mL) under argon atmosphere. The remaining solid was dissolved in anhydrous
toluene (ca. 20 mL) and slowly added to a stirred solution of PCl3 (132 ꢀL, 1.51 mmol) and
NEt3 (476 ꢀL, 3.42 mmol) in dry toluene (ca. 20 mL) at 0 °C. The solution was allowed to reach
room temperature and was stirred overnight. The turbid reaction mixture was filtered and the
solvent evaporated under reduced pressure. The resulting residue was dissolved in ca. 20 mL of
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dry toluene and NEt3 (476 ꢀL, 3.42 mmol). A solution of the diol (R)ꢀD2 (255 mg, 0.55 mmol
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5
6
7
8
in ca. 20 mL of toluene) was slowly added to the previous solution and allowed to react
overnight at room temperature. 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 using acetonitrile/EtOAc 1:1 as elution solvent to get the expected
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bisphosphite ligand (R,S)ꢀL2 as a white solid. Isolated 554 mg, 82% yield, quantitatively pure
by 31P NMR. 1H NMR (CDCl3, 400 MHz): δ 7.82 (s, 1H), 7.80 (s, 1H), 7.76 (s, 1H), 7.74 (s,
1H), 7.32 (s, 1H), 7.29 (s, 1H), 7.25−7.24 (m, 1H), 7.23−7.22 (m, 1H), 7.18−7.09 (m, 8H),
4.01−3.99 (m, 4H), 3.56−3.52 (m, 2H), 3.39−3.36 (m, 4H), 3.20−3.14 (m, 2H), 2.94−2.91 (m,
4H), 2.26 (s, 6H), 2.26 (s, 6H), 1.87 (s, 6H), 1.79 (s, 6H), 1.43 (s, 18H), 1.40 (s, 18H). 13C{1H}
NMR (CDCl3, 125 MHz): δ 154.3, 145.6, 138.2, 137.1, 135.1, 134.4, 134.2, 132.5, 131.9,
131.6, 130.9, 129.5, 129.4, 128.1, 127.9, 127.9, 126.4, 125.6, 123.8, 120.7, 115.8, 70.9, 70.1,
69.5, 63.6, 34.8, 34.8, 31.4, 31.3, 20.6, 20.6, 16.9, 16.7. 31P{1H} NMR: (CDCl3, 202 MHz)
δ 133.8 (s). HRMSꢀESIꢀTOF (m/z
)
: [M+Na]+ calcd for C76H92NaO10P2 1249.6058; found
c
0.1, DCM). IR (neat, cmꢀ1) ῡ 2953, 2868, 1227, 1023. Mp
1249.6037. [ꢀ]ꢂꢁꢃ = +331.2 (
89.3− 90.7 °C.
Synthesis of ligand (S,S)ꢀL3: A mixture of (S)ꢀ[1,1'ꢀbinaphthalene]ꢀ2,2'ꢀdiol (2 g, 6.93 mmol),
2ꢀ(2ꢀhydroxyethoxy)ethyl 4ꢀmethylbenzenesulfonate15 (3.68 g, 13.9 mmol) and K2CO3 (4.12 g,
29.8 mmol) in dry acetonitrile (60 mL) was refluxed for 72 h. The reaction mixture was filtered
and then concentrated under reduced pressure. The crude product was purified by column
chromatography over silica gel (EtOAc/MeOH 95:5 as eluent) to afford (S)ꢀ2,2'ꢀ((([1,1'ꢀ
binaphthalene]ꢀ2,2'ꢀdiylbis(oxy))bis(ethaneꢀ2,1ꢀdiyl))bis(oxy))diethanol ((
S)ꢀD2, see the SI for
the spectra) as a clear brown oil. Isolated 1.5 g, 47% yield. 1H NMR (CDCl3, 500 MHz): δ 7.95
(d,
J = 9.1 Hz, 2H), 7.87 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 9.1 Hz, 2H), 7.35−7.32 (m, 2H),
7.24−7.21 (m, 2H), 7.15 (s, 1H), 7.14 (s, 1H), 4.17−4.13 (m, 2H), 4.03−3.99 (m, 2H), 3.53−3.49
(m, 2H), 3.45−3.40 (m, 6H), 3.22−3.15 (m, 4H), 2.53 (br s, 2H). 13C{1H} NMR (CDCl3, 125
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MHz): δ 154.4, 134.2, 129.6, 129.5, 128.0, 126.5, 125.6, 124.0, 120.8, 116.1, 72.5, 70.0, 69.7,
61.7. HRMSꢀESIꢀTOF (m/z): [M+Na]+ calcd for C28H30NaO6 485.1935; found 485.1927.
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[ꢀ]ꢂꢁꢃ = −25.5 (
c
0.1, DCM). IR (neat, cmꢀ1) ῡ 3419, 2927, 2869, 1240, 1055. Ligand (
S,S)ꢀL3
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was synthesized following the general strategy. (
S
)ꢀ5,5’ꢀ6,6´ꢀtetramethylꢀ3,3´ꢀdiꢀ butylꢀ1,1’ꢀ
t
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biphenylꢀ2,2’ꢀdiol (600 mg, 1.7 mmol) was azeotropically dried with toluene (3 x 2 mL) under
argon atmosphere, dissolved in anhydrous toluene (ca. 23 mL) and slowly added to a stirred
solution of PCl3 (186 ꢀL, 2.13 mmol) and NEt3 (673 ꢀL, 4.84 mmol) in dry toluene (ca. 23 mL)
at 0 °C. The solution was allowed to reach room temperature and was stirred overnight. The
turbid reaction mixture was filtered and the solvent evaporated under reduced pressure. The
resulting residue was dissolved in ca. 23 mL of dry toluene and NEt3 (673 ꢀL, 4.84 mmol). A
solution of the diol (S)ꢀD2 (360 mg, 0.78 mmol in ca. 23 mL of toluene) was slowly added to
the previous solution and allowed to react overnight at room temperature. 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 using acetonitrile/EtOAc 1:1 as elution
solvent to provide the expected bisphosphite ligand (S,S)ꢀL3 as a white solid. Isolated 589 mg,
62% yield, quantitatively pure by 31P NMR. 1H NMR (CDCl3, 500 MHz,): δ 7.83 (s, 1H), 7.81
(s, 1H), 7.77 (s, 1H), 7.75 (s, 1H), 7.30 (s, 1H), 7.28 (s, 1H), 7.27−7.24 (m, 2H), 7.17−7.14 (m,
6H), 7.11 (s, 1H), 7.10 (s, 1H), 4.02−3.97 (m, 4H), 3.52−3.46 (m, 2H), 3.43−3.39 (m, 2H),
3.36−3.31 (m, 2H), 3.20−3.14 (m, 2H), 2.94−2.90 (m, 2H), 2.84−2.81 (m, 2H), 2.26 (s, 12H),
1.86 (s, 6H), 1.79 (s, 6H), 1.42 (s, 18H), 1.39 (s, 18H). 13C{1H,31P} NMR (CDCl3, 125 MHz):
δ 154.3, 145.5, 138.2, 137.1, 135.1, 134.4, 134.2, 132.5, 131.9, 131.6, 130.9, 129.5, 129.4,
128.1, 127.9, 127.9, 126.4, 125.6, 123.8, 120.6, 115.7, 70.9, 70.1, 69.5, 63.8, 34.8, 34.8, 31.4,
31.3, 20.6, 17.0, 16.7. 31P{1H} NMR (CDCl3, 202 MHz): δ 134.7 (s). HRMSꢀESIꢀTOF (m/z
):
[M+Na]+ calcd for C76H92NaO10P2 1249.6058; found 1249.6032. [ꢀ]ꢂꢁꢃ = +279.5 (
IR (neat, cmꢀ1) ῡ 2954, 2867, 1227, 1022. Mp 107.9−109.3 °C.
c 0.1, DCM);
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General procedure for the Rhꢀmediated asymmetric hydroformylations
4
In a glove box filled with nitrogen, to a 2 mL vial equipped with a magnetic bar, ligand L1−3
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7
8
(
ca. 2.7 ꢀmol in 360 ꢀL of toluene), alkali BArF salt (ca. 3.6 ꢀmol in 27 ꢀL of THF), and
[Rh(κ2O,O'ꢀacac)(CO)2] (ca. 2.3 ꢀmol in 65 ꢀL of toluene) were added. Substrate (ca. 230
ꢀmol), and additional toluene were charged getting the mixture toluene/THF (97:3 v/v) and
providing the desired final concentration of substrate 0.26 M. In the cases of vinyl derivatives
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(1a−c) and styrene (1d), nꢀdodecane (ca. 69 ꢀmol) was added as internal standard. The vial was
transferred into an autoclave and taken out of the glove box. The autoclave was purged three
times with syngas (at a pressure not higher than the required for the reaction) and finally, the
autoclave was pressurized with the corresponding pressure of syngas. The reaction mixture was
stirred at 40 °C (water bath) for 18 h. The reaction was cooled and the pressure was carefully
released in a wellꢀventilated hood.
Determination of enantiomeric excesses and configuration of hydroformylated products
Characterization of hydroformylation products of 1a−e, 4, 7 and 8 have been described
previously in the literature and spectroscopic data was in agreement with the reported ones.16
Conversion, regioselectivity and the enantiomeric excesses of hydroformylated products of
vinyl derivatives (1a−c) and styrene (1d) were determined by GC from the crude mixtures,
using
n
ꢀdodecane as internal standard, with a Beta DexTM 225 column (30 m x 0.25 mm x 0.25
1
ꢁm). Conversion and regioselectivity for (allyloxy)trimethylsilane (1e) were determined by H
NMR and the enantiomeric excesses by GC analysis with Beta DexTM 225 column (30 m x 0.25
mm x 0.25 ꢁm) from the crude reaction mixture. Conversion and isomerization of 2,5ꢀ
1
dihydrofuran (4) and 2,3ꢀdihydrofuran (7) were determined by H NMR and the enantiomeric
excesses by GC analysis with Beta DexTM 225 column (30 m x 0.25 mm x 0.25 ꢁm) from the
crude reaction mixture. Conversion and regioselectivity of cisꢀ4,7ꢀdihydroꢀ1,3ꢀdioxepin (8)
1
were determined by H NMR and the enantiomeric excesses were determined by GC from the
crude mixture with a Beta DexTM 225 column (30 m x 0.25 mm x 0.25 ꢁm). Optical rotation of
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aldehyde 9 ([ꢀ]ꢂꢁꢃ = +70.2 (
c 0.1, THF)) was determined from the reaction mixture with a 93%
ee (entry 6 in Table 4) distilling in a Kugelrohr apparatus (40 °C, 5·10ꢀ2 mbar), obtaining the
aldehyde 9 with a final enantiomeric excess of 91% ee (1H NMR spectrum and GC
chromatogram available in the SI).
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Vinyl acetate (1a):17 Temperature program: 100 °C for 5 min, then 4 °C/min to 160 °C.
Retention times: 2.5 min for 1a, 7.2 min for (
R)ꢀ2a, 9.1 min for (S)ꢀ2a, and 12.2 min for 3a.
Vinyl propionate (1b):16a Temperature program: Isothermal 100 °C. Retention times: 2.8 min
for 1b, 9.1 min for (
R)ꢀ2b, 10.5 min for (S)ꢀ2b, and 21.1 min for 3b.
Vinyl benzoate (1c):16a Temperature program: Isothermal 135 °C. Retention times: 6.6 min for
1c, 25.3 min for (
R)ꢀ2c, 27.6 min for (S)ꢀ2c, and 57.3 min for 3c.
Styrene (1d):17 Temperature program: 100 °C for 5 min, then 4 °C/min to 160 °C. Retention
times: 4.6 min for 1d, 12.5 min for (
R)ꢀ2d, 12.8 min for (S)ꢀ2d, and 16.3 min for 3d.
(Allyloxy)trimethylsilane (1e):16d Temperature program: Isothermal 70 °C. Retention times:
24.5 min for (R)ꢀ2e, and 25.6 min for (S)ꢀ2e.
2,5ꢀdihydrofuran (4) and 2,3ꢀdihydrofuran (7):10 Temperature program: 40 °C for 5 min, then
5 °C/min to 150 °C, hold for 1 min; then 10 °C/min to 210 °C. Retention times: 22.7 min for
(R)ꢀ5, and 23.3 min for (S)ꢀ5, 24.7 min for (S)ꢀ6, and 25.6 min for (R)ꢀ6.
cisꢀ4,7ꢀdihydroꢀ1,3ꢀdioxepine (8): Temperature program: 40 °C, hold for 5 min, then 2 °C/min
to 150 °C, hold for 1 min, then 10 °C/min to 210 °C. Retention times: 48.1 min for (+)ꢀ9 and
49.1 min for (−)ꢀ9.18
Direct formation of [Rh(H)(CO)2(κ2P,P’−KBArF·(
)ꢀL1 (12.2 mg, 12.7 ꢀmol), [Rh(κ2O,O'ꢀacac)(CO)2] (3.31 mg, 12.7
S)ꢀL1)]
A 0.03 M solution of (
S
ꢀmol) and KBArF (14.2 mg, 16.5 ꢀmol) in C7D8/C4D8O (97:3 v/v) were transferred to a 25 mL
autoclave reactor, which was pressurized to 10 bar of syngas (1:1 H2/CO) and warmed to 40 °C.
The mixture was allowed stirring for 2 hours. The reactor was cooled to room temperature,
depressurized in a wellꢀventilated fume hood and the reaction mixture was transferred to a 5
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mm HPꢀNMR sapphire tube. The tube was pressurized with syngas (1:1 H2/CO, 10 bar) and the
HPꢀNMR spectra were collected at 25 °C (see SI). MS samples were immediately recorded
under N2 after depressurizing the autoclave. Spectroscopic data obtained from this solution was
8
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in agreement with the quantitative formation of the [Rh(H)(CO)2(κ2P,P´−ΚΒArF·(
S)ꢀL1)]
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complex: 1H NMR (C7D8/C4D8O (97:3 v/v), 500 MHz): δ 7.23 (s, 2H), 7.16 (s, 2H), 3.90−3.88
(m, 2H), 3.37−3.34 (m, 2H), 2.95−2.85 (m, 10H), 2.67−2.64 (m, 2H), 2.11 (s, 6H), 1.98 (s, 6H),
1.65 (s, 6H), 1.58 (s, 6H), 1.52 (s, 18H), 1.48 (s, 18H), −10.83 (d, JPH = 4.8 Hz, 1H). 13C{1H}
NMR (C7D8/C4D8O (97:3 v/v), 125 MHz): δ 191.2, 147.6, 144.5, 136.1, 136.0, 135.7, 134.9,
133.7, 133.5, 130.6, 130.3, 130.0, 129.8, 129.6, 129.1, 126.4, 118.7, 69.6, 69.5, 69.4, 67.0, 35.6,
34.9, 33.0, 31.2, 20.2, 20.0, 16.3, 16.3. 31P NMR (C7D8/C4D8O (97:3 v/v), 202 MHz): δ 142.6
(d, JRhP = 242.9 Hz). HRMSꢀMALDIꢀTOF (m/z): [M−H−CO−K]+ calcd for C57H80O10P2Rh
1089.4276, found 1089.4264. Attempts to isolate this complex in analytically pure form failed.
Direct formation of [Rh(H)(CO)2(κ2P,P’−KBArF·(
)ꢀL2 (11.6 mg, 9.47 ꢀmol), [Rh(κ2O,O'ꢀacac)(CO)2] (2.47 mg, 9.47
R,S)ꢀL2)]
A 0.02 M solution of (R,S
ꢀmol) and KBArF (10.6 mg, 12.3 ꢀmol) in C7D8/C4D8O (97:3 v/v) were transferred to a 25 mL
autoclave reactor, which was pressurized to 10 bar of syngas (1:1 H2/CO) and warmed to 40 °C.
The mixture was allowed stirring for 2 hours. The reactor was cooled to room temperature,
depressurized in a wellꢀventilated fume hood and the reaction mixture was transferred to 5 mm
HPꢀNMR sapphire tube. The tube was pressurized with syngas (1:1 H2/CO, 10 bar) and the HPꢀ
NMR spectra were collected at 25 °C (see SI). MS samples were immediately recorded under
N2 after depressurizing the autoclave. Spectroscopic data obtained from this solution was in
agreement with the quantitative formation of the [Rh(H)(CO)2(κ2P,P´−ΚΒArF·(
R,S)ꢀL2)]
1
complex: H NMR (C7D8/C4D8O (97:3 v/v), 500 MHz): δ 7.79 (s, 1H), 7.77 (s, 1H), 7.66 (s,
4H), 7.25 (s, 1H), 7.23 (s, 3H), 7.20−7.17 (m, 2H), 7.15 (s, 2H), 7.00 (s, 2H), 3.94−3.92 (m,
2H), 3.51−3.48 (m, 2H), 3.26−3.22 (m, 2H), 3.07−2.97 (m, 4H), 2.75−2.72 (m, 2H), 2.37−2.35
(m, 2H), 2.24−2.22 (m, 2H), 2.11 (s, 6H), 2.00 (s, 6H), 1.64 (s, 6H), 1.63 (s, 6H), 1.51 (s, 18H),
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1.43 (s, 18H), −10.38 (br s, 1H). 13C{1H} NMR (C7D8/C4D8O (97:3 v/v), 125 MHz): δ 191.1,
154.0, 146.9, 144.3, 136.1, 136.1, 134.4, 133.8, 133.6, 131.5, 131.4, 131.0, 130.0, 130.0, 129.8,
126.4, 126.1, 125.8, 124.2, 123.3, 122.0, 119.6, 71.1, 70.4, 69.7, 66.6, 35.6, 34.8, 32.9, 31.1,
20.1, 20.0, 16.4, 16.3. 31P NMR (C7D8/C4D8O (97:3 v/v), 202 MHz): δ 143.8 (dd, JRhP = 234.4
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Hz; JPH = 22.8 Hz). HMRSꢀMALDIꢀTOF (m/z)
: [M−H−CO−K]+ calcd for C77H92O11P2Rh
1357.5164, found 1357.5135. Attempts to isolate this complex in analytically pure form failed.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: avidal@iciq.cat
ACKNOWLEDGEMENT
The authors would like to thank MINECO (CTQ2014ꢀ60256ꢀP) and the ICIQ Foundation for
their financial support. Funding from the CELLEX Foundation through the CELLEXꢀICIQ high
throughput experimentation platform is also gratefully acknowledged. L.R. would like to thank
the ICIQ Foundation for a preꢀdoctoral fellowship. Dr. M. V. is grateful for the financial support
received from the CELLEX Foundation.
ASSOCIATED CONTENT
Supporting Information: Extended tables of AHF reactions, NMR spectra and chromatograms
on chiral stationary phases. This material is available free of charge via the Internet at
http://pubs.acs.org.
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ꢀ
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7
18) The racemic mixture of the hydroformylated product derived from 8 was prepared using
the Xantphos ligand (see SI for details).
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