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Asymmetric Hydroformylation of Heterocyclic Olefins Mediated by
Supramolecularly Regulated Rhodium-Bisphosphite Complexes
Laura Rovira†, Mónica Vaquero† and Anton Vidal-Ferran †‡*
†

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.

Supporting Information
Abstract: Rhodium complexes derived from conformationally transformable -bisphosphite ligands combined with a

reinforces the regulation ability of the catalysts and leads to
efficient AHF catalysts for a number of heterocyclic olefins.

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.

The new ligands, (R,S)-L2 and (S,S)-L3, were synthesized by
6
O-phosphorylation of the corresponding diol derivatives.
Ligand (S)-L1, which lacks a stereogenic element in the regulation site, was also considered in order to aid comparison
and was synthesized in an analogous manner (see the Experimental Section).

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
1
coordination sphere of a chiral catalyst. However, there are
few examples of the fine modification of the geometry of the
2,3
active site. 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. Iondipole 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
2
metal center. Furthermore, the library of catalysts arising
upon the binding of an array of RAs to the regulation site not
only preserves most of the structural characteristics but also
incorporates structural peculiarities that depend on the size
and shape of the RA employed. Hydroformylation is an attractive industrial process requiring transition metal cata4
lysts, from which rhodium complexes derived from bisphosphite ligands have been used with variable success in the
5
hydroformylation of heterocyclic alkenes. 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

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 and Table
2
1). Initial studies were performed with [Rh(  O,O´acac)(CO)2] and the corresponding ligand at 40 C under 10
bar syngas in toluene, with the minimum amount of THF to
2a c
solubilize the RA.  The results on AHF are partially summarized in Table 1, which summarizes the results for the
7
catalysts that show the highest positive regulation effects. 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), whereas 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

8

9

synthesis of biologically relevant products. Our group and
5b,8a,10
10d
others have studied the AHF of five-,
six-, and seven-

5b,10a,c

membered heterocyclic olefins and reported problems
in the control of chemo- and regioselectivity.

Scheme 1. Supramolecularly regulated bisphosphite ligands with a distal regulation site.
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 tetrahydrofuran-2-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).
Table 1. AHF of 1ae using the catalysts that lead to the
a
highest regulation effects
Scheme 2. AHF of compounds 1ae mediated by supramolecularly regulated ligands L13.

entry

ligand

substrate

1

(R,S)L2

1a

(R,S)L2

1b

(S)-L1

1c

(S,S)L3

1d

In the AHF of 2,5-dihydrofuran, the expected tetrahydrofuran-3-carbaldehyde (6), the regioisomeric aldehyde 5 and 2,3dihydrofuran (7) can be formed (Scheme 3 and Table 2). The
latter compound arises from a CC bond isomerization that
11
occurs simultaneously with the hydroformylation.
Supramolecularly regulated ligands L13 proved to be very
active in the AHF of 2,5-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 in 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 tetrahydrofuran-2-carbaldehyde
(5/6 ratio from 1:92 to 35:39; compare entries 6 and 8 in Table
2); 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 2,3-dihydrofuran under the
same conditions was also studied (see Scheme 3 and Table 3).

2
3
4
5
6
7
8
9
10

(S,S)L3

1e

ee of 2
(%)
config.

conv
(%)

b/l
ratio

-

92

>99:1

23(R)

RbBArF

>99

>99:1

92(R)

RA

-

94

>99:1

15 (R)

KBArF

>99

>99:1

92(R)

-

90

>99:1

7 (S)

NaBArF

78

98:2

76(R)

-

>99

95:5

42(R)

NaBArF

>99

96:4

b

-

>99

CsBArF

>99b

54(R)

b

17 (R)

18:82b

23(R)

61:39

a

Reaction conditions are shown in Scheme 2. Conversion was
determined by GC chromatography ( -Dex 225) using n-dodecane
as internal standard unless otherwise stated. The ratio of the regioisomers and ee values were determined by GC analysis on a chiral
stationary phase-Dex 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.

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 mixture on the outcome of the AHF of 4. We also
hoped to be able to identify the AHF conditions that lead 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).

in AHF, which reduce control of regio- and enantioselectivi11
ty.
Table 3. AHF of 7 using Rh-complexes of ligands L13 and a
a
set of BArF salts as RAs.

entry

ligand

RA

conv.

ratio

(%)

5:6:7

ee of 5

ee of 6

(%)

(%)

config.

config.

1

-

7

2:5:93

5 (S)

26 (S)

2

NaBArF

31

18:13:69

62 (R)

44 (R)
8 (S)

3

entry

ligand

RA

(%)

5:6:7

ee of 5

config.

1

-

>99

2:93:5

23 (S)

NaBArF

92

5:73:22

60 (R)

(S)-L1

>99

21:15:64

74 (R)

>99

25:31:44

77 (R)

CsBArF

>99

13:72:15

52 (R)

15 (R)

6

-

>99

1:92:7

11 (S)

36 (R)

7
8

NaBArF
(R,S)L2

98

1:91:8

2 (S)

25 (R)

KBArF

>99

35:39:26

82 (R)

57:32:11

56 (R)

6 (S)
16 (S)

-

32

12:20:68

13 (S)

NaBArF

40

17:23:60

3 (S)

8 (R)

KBArF

65

52:13:35

81 (R)

20 (R)
10 (R)

(R,S)L2

RbBArF

57

48:9:43

79 (R)

CsBArF

40

33:7:60

75 (R)

rac

-

29

10:19:71

11 (S)

14 (S)

12

NaBArF

31

11:20:69

24 (S)

15 (S)

13

21 (S)

5

89

11

60 (S)

RbBArF

4

KBArF

2 (S)

CsBArF

10

61 (S)

3

79 (R)

9

38 (R)

2

76 (R)

34:5:61

8

(%)

config.

21:2:77

39

7

ee of 6

(%)

(S)-L1

6

Table 2. AHF of 4 using Rh-complexes of ligands L13 and a
a
set of BArF salts as RAs.
ratio

23

RbBArF

5

conv.

KBArF

4

Scheme 3. AHF of 4 and 7 mediated by supramolecularly
regulated ligands L13.

KBArF

50

30:20:50

19 (R)

rac

RbBArF

32

22:10:68

44 (R)

13 (S)

CsBArF

28

19:9:73

44 (R)

16 (S)

14
15

(S,S)L3

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.

56 (S)
52 (S)

9

RbBArF

>99

34:26:40

81 (R)

10

CsBArF

>99

19:38:43

76 (R)

14 (S)

11

-

98

1:90:9

10 (S)

38 (R)

NaBArF

>99

1:97:2

34 (S)

42 (R)

KBArF

96

3:85:12

18 (R)

2 (S)

12
13

(S,S)L3

14

RbBArF

93

4:69:27

45 (R)

13 (S)

15

CsBArF

97

5:70:25

43 (R)

18 (R)

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 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 S6 and Figure S1 in the Supporting In12
formation). 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).
Ligands L13 were also tested in the AHF of six-membered
heterocyclic olefins (see Supporting Information 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

Figure 1. AHF of 4 at 5 bar with different syngas mixtures.

Finally, ligands (S)-L1, (R,S)-L2 and (S,S)-L3 were tested in
the AHF of cis-4,7-dihydro-1,3-dioxepin (8) with a set of
alkali BArF salts as RAs (see Scheme 4 and Table 4).
The reactions showed complete regioselectivity toward
product 9 (see Table 4 and S8). The use of RAs led to a great
improvement in the conversion (up to 82%) and enantioselectivity (up to 79%). The highest enantioselectivities were
obtained with combinations (S)-L1/NaBArF (85% ee), (R,S)-

L2/KBArF (83% ee), and (S,S)-L3/RbBArF (74% ee) (entries 2,
5, and 8, respectively, in 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
10a
knowledge, is the highest reported for this substrate.

Scheme 4. AHF of 8 mediated by supramolecularly regulated
ligands L13.

account for the higher activity of ligand (R,S)-L2 in the AHF
of heterocyclic alkenes.
In summary, challenging heterocyclic olefins were efficiently
hydroformylated in terms of high regio- and enantioselectivities with supramolecularly regulated rhodium complexes
derived from bisphosphite ligands L13. Small amounts of
polyether-binder 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 2,5dihydrofuran, we have demonstrated the potential of our
supramolecularly regulated catalysts, as the use of an alkali
metal BArF salt as RA increased enantioselectivity (up to 33%
ee), reversed the regioselectivity of the reaction, or completely suppressed the formation of the side-product.
EXPERIMENTAL SECTION

Table 4. AHF of 8 using Rh-complexes of ligands L13 and a
a
set of BArF salts as RAs.
entry

-

28

6 (+)

>99

85 (+)

NaBArFc

95

92 (+)

-

7

23

10 (-)

KBArF

>99

83 (+)

KBArFc

(R,S)-L2

6

9

(%)b

NaBArF

4

8

(%)

(S)-L1

3
5

ee of 9

RA

1
2

conv.

ligand

>99

93 (+)

(S,S)-L3

17

rac

RbBArF

>99

74 (+)

RbBArFc

93

89 (+)

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, complexa2
tion experiments between [Rh( O,O´-acac)(CO2)], ligand
(R,S)-L2, and one representative RA (KBArF) were performed. These compounds were reacted at 40 C under 10
bar of 1:1 H2/CO. Interestingly, the expected hydrido2
dicarbonyl chelate [Rh(H)(CO)2( P,P´ArF●(R,S)-L2)]
13
was efficiently formed. NMR analysis showed the hydrido
signal as a broad and partially resolved multiplet centered at
2
10.38 ppm ( JPH = 22 Hz). The value of this coupling constant indicates that the system undergoes an equilibrium
between two hydrido-dicarbonyl rhodium complexes with
the two P-ligating groups coordinated in an equatorialequatorial or apicalequatorial fashion to a trigo14
nalbipyramidal rhodium center. The complexation behavior of ligand (R,S)-L2 is different from that of ligand (S)-L1,
which lacks the biaryl core in the regulation site. NMR analysis on the hydrido-dicarbonyl chelate derived from (S)-L1
indicated that the two P-ligating groups coordinated in an
14
equatorialequatorial fashion (see Experimental Section
and Supporting Information). This difference in coordination
behavior between ligands with or without the [1,1'binaphthalene]-2,2'-diol motif in the regulation site could

General information: All syntheses were carried out using
chemicals as purchased from commercial sources unless
otherwise cited. All manipulations and reactions were performed under an 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 Silica-C18 (200400
mesh) were used for column chromatography. NMR spectra
1
13
were recorded in CDCl3 unless otherwise cited. H and C
NMR chemical shifts are quoted in ppm relative to residual
31
solvent peaks, whereas P NMR chemical shifts are quoted in
ppm relative to 85% phosphoric acid in water. IR spectra
were recorded using attenuated total reflection (ATR) unless
otherwise cited. High-resolution mass spectra (HRMS) were
recorded using an electrospray ionization (ESI) method in
positive mode for the ligands (L13) and diols ((R)-D2 and
(S)-D2) and matrix-assited laser desorption ionization
(MALDI)
in
positive
mode
for
2
[Rh(H)(CO)2( P,P´ArF●(S)-L1)]
and
2
[Rh(H)(CO)2( P,P´ArF●(R,S)-L2)], using, in all cases, a
time-of-flight (TOF) detector. 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´-Tetramethyl-3,3´di-tert-butyl-1,1’-biphenyl-2,2’-diol (265 mg, 0.75 mmol) was
azeotropically dried with toluene (3 × 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 the mixture was allowed to react
overnight at room temperature. The reaction mixture was
filtered, and the solvent was evaporated under reduced pressure. The resulting crude mixture was purified by column
chromatography on silica gel C18 using acetonitrile/EtOAc 1:1
as the elution solvent to obtain the expected bisphosphite

1

ligand (S)-L1 as a white solid. Isolated 312 mg, 83% yield. H
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), 2.25 (s, 6H),
2.24 (s, 6H), 1.85 (s, 6H), 1.78 (s, 6H), 1.45 (s, 18H), 1.42 (s,
13
1
18H). C{ H} 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 1
31.3, 20.6, 16.9, 16.7. P{ H} NMR (CDCl3, 202 MHz): δ 132.6
+
(s). HRMS-ESI-TOF (m/z): [MNa] calcd for C56H80O9P2Na,
25
981.5170; found, 981.5191. [𝛼]D = 371.8 (c 0.1, DCM). IR (neat,
-1
cm ) ῡ2963, 2867, 1254, 1027, 870.mp 71.272.6 C.
Synthesis of ligand (R,S)-L2: A mixture of (R)-[1,1'binaphthalene]-2,2'-diol (1.75 g, 6.13 mmol), 2-(215
hydroxyethoxy)ethyl-4-methylbenzenesulfonate (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(ethane-2,1-diyl))bis(oxy))diethanol ((R)-D2;
see the Supporting Information for the spectra) as a clear
1
brown oil. Isolated 1.33 g, 46% yield. H NMR (CDCl3, 500
MHz,):  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), 7.16
(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
13
1
(t, J = 6.6 Hz, 2H). C{ H} NMR (CDCl3, 125 MHz):  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. HRMS-ESI-TOF (m/z): [MNa] calcd for
25
C28H30NaO6, 485.1935; found, 485.1923. [𝛼]D = 43.1 (c 0.1,
-1
DCM). IR (neat, cm ) ῡ 3414, 2927, 2869, 1240, 1054. Ligand
(R,S)-L2 was synthesized from (S)-5,5’-6,6´-tetramethyl-3,3´di-tert-butyl-1,1’-biphenyl-2,2’-diol (424 mg, 1.2 mmol), which
was azeotropically dried with toluene (3 × 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 dry toluene and NEt3 (476 L, 3.42
mmol). A solution of the diol (R)-D2 (255 mg, 0.55 mmol in
ca. 20 mL of toluene) was slowly added to the previous solution, and the mixture was 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 the elution solvent to obtain the expected bisphosphite ligand (R,S)-L2 as a
white solid. Isolated 554 mg, 82% yield, quantitatively pure
31
1
by P NMR. H NMR (CDCl3, 400 MHz):  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).
13
1
C{ H} NMR (CDCl3, 125 MHz): 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,
31 1
34.8, 31.4, 31.3, 20.6, 20.6, 16.9, 16.7. P{ H} NMR: (CDCl3, 202

MHz) 133.8sHRMS-ESI-TOF (m/z): [M+Na] calcd for
C76H92NaO10P2, 1249.6058; found, 1249.6037. [𝛼]25 = 331.2 (c
D
-1
0.1, DCM). IR (neat, cm ) ῡ295386812271023. mp
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),
2-(215
hydroxyethoxy)ethyl-4-methylbenzenesulfonate
(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(ethane-2,1diyl))bis(oxy))diethanol ((S)-D2, see the Supporting Information for the spectra) as a clear brown oil. Isolated 1.5 g,
1
47% yield. H NMR (CDCl3, 500 MHz): 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,
13
1
6H), 3.223.15 (m, 4H), 2.53 (br s, 2H). C{ H} NMR (CDCl3,
125 MHz):  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. HRMS-ESI-TOF (m/z):
+
[MNa] calcd for C28H30NaO6, 485.1935; found, 485.1927.
-1
25
[𝛼]D = 25.5 (c 0.1, DCM). IR (neat, cm ) ῡ 3419, 2927, 2869,
1240, 1055. Ligand (S,S)-L3 was synthesized following the
general strategy. (S)-5,5’-6,6´-tetramethyl-3,3´-di-tert-butyl1,1’-biphenyl-2,2’-diol (600 mg, 1.7 mmol) was azeotropically
dried with toluene (3 × 2 mL) under an 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 was evaporated under reduced pressure. The resulting crude mixture was purified by column chromatography
on silica gel C18 using acetonitrile/EtOAc 1:1 as the elution
solvent to provide the expected bisphosphite ligand (S,S)-L3
as a white solid. Isolated 589 mg, 62% yield, quantitatively
31
1
pure by P NMR. H NMR (CDCl3, 500 MHz,):  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 (m, 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
13
1
31
(s, 18H), 1.39 (s, 18H). C{ H, P} NMR (CDCl3, 125 MHz):
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.
31 1
P{ H} NMR (CDCl3, 202 MHz): 134.7sHRMS-ESI-TOF
+
(m/z): [M+Na] calcd for C76H92NaO10P2, 1249.6058; found,
-1
25
1249.6032. [𝛼]D = 279.5 (c 0.1, DCM). IR (neat, cm )
ῡ295486712271022. mp 107.9109.3 °C.
General procedure for Rh-mediated asymmetric hydroformylations

To a 2 mL vial equipped with a magnetic bar in a glovebox
filled with nitrogen were added ligand L13 (ca. 2.7 mol in
360 L of toluene), alkali BArF salt (ca. 3.6 mol in 27 L of
2
THF), and [Rh( O,O'-acac)(CO)2] (ca. 2.3 mol in 65 L of
toluene). Substrate (ca. 230 mol) and additional toluene
were charged, obtaining 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 (1ac) and styrene
(1d), n-dodecane (ca. 69 mol) was added as an internal
standard. The vial was transferred into an autoclave and
taken out of the glovebox. The autoclave was purged three
times with syngas (at a pressure not higher than that 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 well-ventilated 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
16
spectroscopic data were in agreement with those reported.
Conversion, regioselectivity and 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 an internal standard, with a -Dex
225 column (30 m × 0.25 mm × 0.25 μm). Conversion and
regioselectivity for (allyloxy)trimethylsilane (1e) were deter1
mined by H NMR, and the enantiomeric excesses, by GC
analysis with -Dex 225 column (30 m × 0.25 mm × 0.25 μm)
from the crude reaction mixture. Conversion and isomerization of 2,5-dihydrofuran (4) and 2,3-dihydrofuran (7) were
1
determined by H NMR, and the enantiomeric excesses, by
GC analysis with -Dex 225 column (30 m × 0.25 mm × 0.25
μm) from the crude reaction mixture. Conversion and regioselectivity of cis-4,7-dihydro-1,3-dioxepin (8) were deter1
mined by H NMR, and enantiomeric excesses, by GC from
the crude mixture with a -Dex 225 column (30 m × 0.25 mm
× 0.25 μm). Optical rotation of aldehyde 9 ([𝛼]25 = 70.2 (c
D
0.1, THF)) was determined from the reaction mixture with a
93% ee (entry 6 in Table 4) distilling in a Kugelrohr appa-2
ratus (40 °C, 5 × 10 mbar), obtaining aldehyde 9 with a final
1
enantiomeric excess of 91% ee ( H NMR spectrum and GC
chromatogram are available in the Supporting Information).
17

Vinyl acetate (1a): 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.
16a

Vinyl propionate (1b): 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.
16a

Vinyl benzoate (1c): 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.
17

Styrene (1d): 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.
16d

(Allyloxy)trimethylsilane (1e): Temperature program: Isothermal 70 °C. Retention times: 24.5 min for (R)-2e, and 25.6
min for (S)-2e.

9

2,5-dihydrofuran (4) and 2,3-dihydrofuran (7): Temperature
program: 40 °C for 5 min, 5 °C/min to 150 °C, hold for 1 min,
and 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.
cis-4,7-dihydro-1,3-dioxepin (8): Temperature program: 40
°C, hold for 5 min, 2 °C/min to 150 °C, hold for 1 min, and
then 10 °C/min to 210 °C. Retention times: 48.1 min for ()-9
18
and 49.1 min for ()-9.
Direct formation of [Rh(H)(CO)2( P,P’KBArF·(S)-L1)]
2

A 0.03 M solution of (S)-L1 (12.2 mg, 12.7 mol), [Rh( O,O'acac)(CO)2] (3.31 mg, 12.7 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
to stir for 2 h. The reactor was cooled to room temperature
and depressurized in a well-ventilated fume hood, and the
reaction mixture was transferred to 5 mm HP-NMR sapphire
tube. The tube was pressurized with syngas (1:1 H2/CO, 10
bar) and the HP-NMR spectra were collected at 25 °C (see
Supporting Information). 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
2
1
[Rh(H)(CO)2( P,P´ArF·(S)-L1)] complex: H NMR
(C7D8/C4D8O (97:3 v/v), 500 MHz): 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,
13
1
1H) C{ H} NMR (C7D8/C4D8O (97:3 v/v), 125 MHz):  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,
31
35.6, 34.9, 33.0, 31.2, 20.2, 20.0, 16.3, 16.3. P NMR
(C7D8/C4D8O (97:3 v/v), 202 MHz):  142.6 (d, JRhP = 242.9
Hz). HMRS-MALDI-TOF (m/z): [MHCOK] calcd for
C57H80O10P2Rh, 1089.4276, found, 1089.4264. Attempts to
isolate this complex in analytically pure form failed.
2

Direct formation of [Rh(H)(CO)2( P,P’KBArF·(R,S)L2)]
2

A 0.02 M solution of (R,S)-L2 (11.6 mg, 9.47 mol),
2
[Rh( O,O'-acac)(CO)2] (2.47 mg, 9.47 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 to stir for 2 h. The reactor was cooled to
room temperature and depressurized in a well-ventilated
fume hood, and the reaction mixture was transferred to 5
mm HP-NMR sapphire tube. The tube was pressurized with
syngas (1:1 H2/CO, 10 bar) and the HP-NMR spectra were
collected at 25 °C (see Supporting Information). 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
2
1
[Rh(H)(CO)2( P,P´ArF·(R,S)-L2)] complex: H NMR
(C7D8/C4D8O (97:3 v/v), 500 MHz):  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), 1.43 (s, 18H), 10.38 (br

s, 1H) C{ H} NMR (C7D8/C4D8O (97:3 v/v), 125 MHz): 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.P NMR (C7D8/C4D8O (97:3 v/v), 202 MHz):  143.8 (dd,
JRhP = 234.4 Hz; JPH = 22.8 Hz). HMRS-MALDI-TOF (m/z):
+
[MHCOK] calcd for C77H92O11P2Rh, 1357.5164, found,
1357.5135. Attempts to isolate this complex in analytically
pure form failed.
13

1

ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01805.
Extended tables of AHF reactions, NMR spectra, and chromatograms on chiral stationary phases (PDF).
AUTHOR INFORMATION
Corresponding Author
*E-mail: avidal@iciq.cat Phone: +34 977920210. Fax: + 34
977920228.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors would like to thank MINECO (CTQ2014-60256P) and the ICIQ Foundation for financial support. Funding
from the CELLEX Foundation through the CELLEX-ICIQ
high-throughput experimentation platform is also gratefully
acknowledged. L.R. would like to thank the ICIQ Foundation
for a predoctoral fellowship. M. V. is grateful for the financial
support received from the CELLEX Foundation.
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Organomet. Chem. 2000, 608, 115-121.
14) Small PH couplings indicate that the hydrido ligand has a
strong preference for a cis-orientation relative to the P-ligating
groups, which are coordinated in an equatorialequatorial fashion to
a trigonalbipyramidal rhodium center. See, for example: (a) Nozaki,
K.; Sakai, N.; Nanno, T.; Higashijima, T.; Mano, S.; Horiuchi, T.;
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16) Spectroscopic data of hydroformylated products: For 2ab,
see: (a) Zhang, X.; Cao, B.; Yan, Y.; Yu, S.; Ji, B.; Zhang, X. Chem.-Eur.
J. 2010, 16, 871-877. For 2c, see: (b) Kano, T.; Mii, H.; Maruoka, K. J.
Am. Chem. Soc. 2009, 131, 3450-3451. For 2d, see: (c) Friest, J. A.;
Maezato, Y.; Broussy, S.; Blum, P.; Berkowitz, D. B. J. Am. Chem. Soc.
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17) (a) Cobley, C. J.; Klosin, J.; Qin, C.; Whiteker, G. T. Org. Lett.
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T. Org. Lett. 2005, 7, 1197
18) The racemic mixture of the hydroformylated product derived
from 8 was prepared using the Xantphos ligand (see Supporting
Information for details).