New diphosphite ligands for enantioselective asymmetric hydroformylation

Article abstract of DOI:10.1016/j.tetlet.2007.04.117

A series of new diphosphite ligands have been easily prepared from BINOL derivatives; moderate enantioselectivities (up to 80% ee) and excellent regioselectivities (b/l up to 98/2) have been achieved in the Rh-catalyzed asymmetric hydroformylation of vinyl acetate.

Full text of DOI:10.1016/j.tetlet.2007.04.117

Tetrahedron Letters 48 (2007) 4781–4784
New diphosphite ligands for enantioselective asymmetric
hydroformylation
Yaping Zou, Yongjun Yan and Xumu Zhang*
104 Chemistry Building, Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
Received 21 March 2007; revised 17 April 2007; accepted 24 April 2007
Available online 29 April 2007
Abstract—A series of new diphosphite ligands have been easily prepared from BINOL derivatives; moderate enantioselectivities (up
to 80% ee) and excellent regioselectivities (b/l up to 98/2) have been achieved in the Rh-catalyzed asymmetric hydroformylation of
vinyl acetate.
Ó 2007 Elsevier Ltd. All rights reserved.
Homogeneous catalytic hydroformylation has been
extensively applied in the fine chemical and pharmaceu-
tical industry. Asymmetric hydroformylation1 provides
a highly efficient method for the preparation of various
chiral aldehydes, which can be utilized in the synthesis of
important drug intermediates and pharmaceuticals. This
great demand has initiated tremendous efforts in the
development of effective phosphorus ligands to achieve
both high enantioselectivities and regioselectivities in
hydroformylation. However, to date only a few success-
ful ligand systems have been previously reported.2 One
such example is Chiraphite, a bisphosphite ligand devel-
oped by Babin and Whiteker at Union Carbide in
1992.2a,3 Excellent enantioselectivities (up to 90% ee)
have been achieved in the hydroformylation of styrene,
but only moderate enantioselectivities (up to 50% ee)
were reported for vinyl acetate. The chiral centers in
the (2R,4R)-pentane-2,4-diol backbone can effectively
transfer the chiral information to the phosphite moie-
ties. The presence of bulky substituents (t-butyl) at the
ortho-position of the biphenyl moieties is necessary for
good regio- and enantioselectivities. Kelliphite, another
diphosphite ligand which is not only a good ligand for
hydroformylation of allyl cyanide,2f but also exhibits
high enantioselectivity (88% ee at 35 °C) in the hydro-
formylation of vinyl acetate.4 The chiral phosphite moi-
eties, which are connected by the bis-phenol bridge,
determine the chirality of the product.
Prompted by the excellent results obtained with Chi-
raphite and Kelliphite, we have designed a series of
new diphosphite ligands using chiral binaphthyl as the
backbone. The ligand design was based on the following
considerations: (i) ligand bearing binaphthyl backbone
such as BINAP can provide excellent chiral induction
in asymmetric reactions;5 (ii) introduction of substitutes
at 3,30-position on binaphthyl backbone can lock the
orientation of biphenyl groups of the phosphite moie-
ties, which can facilitate highly enantioselective hydro-
formylation; (iii) subtle tuning of steric and electronic
properties of the ligand can be achieved by varying the
substitutes on 3,30-position.
The synthetic route for ligand L1–L4 is depicted in
Scheme 1.6 In the presence of catalytic amount of 1-
methylpyrrolidin-2-one, reaction of PCl3 with 3,30-bis-
t-butyl biphenol 1 at 95 °C for 18 h afforded phosphoro-
chloridite 2, which was used in the next step without fur-
ther purification.7 (S) BINOL derivative 3 with different
3,30-substitutes were synthesized according to the
known literature methods.8 Deprotonation of 3 with n-
butyl lithium followed by quenching with phosphoro-
chloridite 2 afforded (S) ligands L1–L4 in moderate
yields.9
Rhodium-catalyzed asymmetric hydroformylation of
vinyl acetate was conducted for preliminary examina-
tions of the four ligands. The catalyst was prepared
in situ by mixing Rh(acac)(CO)2 with L1–L4. Hydro-
formylation reactions were performed using 1:1 CO/H2
gas with 0.1 mol % of the catalyst loading at 40 °C for
24 h.10 Screening of ligands L1–L4 showed a strong
*
Corresponding author. Tel.: +1 732 445 2674; fax: +1 732 445
6312; e-mail: xumu@chem.psu.edu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.117

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Y. Zou et al. / Tetrahedron Letters 48 (2007) 4781–4784
t-Bu
t-Bu
t
-Bu
t
-Bu
O
O
O O
O
OMe
O
P
P
P
O
O
P
MeO
O
O
O
t
O
t-Bu
t-Bu
t
-Bu
-Bu
OMe
MeO
(S,S) Kelliphite
(2R, 4R)-chiraphite
t
-Bu
t
-Bu
R
O
O
O
R
P
P
O
t-Bu
t-Bu
O
O
t
t
-Bu
-Bu
t-Bu
t-Bu
New ligands
dependence of ee’s on the substitutes on 3,30-positions of
the ligands. The best results were obtained by L2 and L3
(Table 1, entries 2 and 3), while the enantioselectivities
were significantly lower using L1 and L4 (Table 1, entries
1 and 4). This results implies that the steric properties of
3,30-substitutes may play an important role in the chiral
induction. Good to excellent regioselectivities were also
achieved using these ligands (Table 1, entries 1–4).
was first investigated. As shown in Table 2 (entries 1
and 3), the enantioselectivity increased from 35% ee to
77% ee when ligand/metal ratios increased from 1:1 to
4:1. Higher ligand/metal ratio (6:1) did not improve
the enantioselectivity (Table 2, entry 4). The reaction
was also examined at higher temperature to achieve
good conversions. In contrast to the moderate catalytic
activity observed at 60 °C (43%, 72% ee, Table 2, entry
5), close to complete conversion was achieved at 80 °C
though with diminished enantioselectivity (56% ee,
Table 2, entry 6), but regioselectivities did not change
significantly. The enantioselectivity in asymmetric hyd-
Reaction conditions were optimized using L2 as the
ligand and the results are shown in Table 2. The effect
of ligand/metal ratio on the hydroformylation reaction
t
t
-Bu
-Bu
t
-Bu
t
-Bu
-Bu
t-Bu
a
OH
OH
O
O
P
Cl
t-Bu
t
t-Bu
1
2
R
b
t
-Bu
t
-Bu
R
OH
OH
O O
R
P
O
P
O
t
-Bu
t
-Bu
O
O
R
3
t-Bu
t-Bu
t-Bu
t-Bu
L1 R = H 43%
L2 R = Ph 55%
L3 R = Me 37%
L4 R = Br 26%
3a
R = H
3b
3c
3d
R = Ph
R = Me
R = Br
Scheme 1. Synthesis of diphosphite ligands L1–L4. Reagents and conditions: (a) PCl3, 1-methylpyrrolidin-2-one, 95 °C, toluene; (b) (i) n-BuLi
(1.5 equiv), THF; (ii) 2 (1.5 equiv), 20–60%.

Y. Zou et al. / Tetrahedron Letters 48 (2007) 4781–4784
4783
Table 1. Screening of ligands for asymmetric hydroformylationa
been achieved. However, low enantioselectivites (less
than 30% ee) were obtained for the hydroformylation
of styrene. Further ligand structure modifications are
currently undergoing to increase the enantioselectivity
and the reactivity.
CHO
Rh(acac)(CO)2 /ligand
*
OAc
OHC
+
OAc
OAc
eed (%)
CO/H2, toluene
Entry
Ligand
Conv.b (%)
b/lc
1
2
3
4
L1
L2
L3
L4
29
23
45
23
96/4
97/3
98/2
98/2
13(S)
71(S)
75(S)
16(S)
References and notes
´
1. For recent reviews, see: (a) Claver, C.; Dieguez, M.;
`
´
Pamies, O.; Castillon, S. Top. Organometall. Chem. 2006,
a Reactions were carried out under 10 atom of H2 and CO at 40 °C for
24 h. Substrate/Rh = 1000. L/Rh = 4:1.
´
`
18, 35; (b) Dieguez, M.; Pamies, O.; Claver, C. Tetra-
hedron: Asymmetry 2004, 15, 2113; (c) Agbossou, F.;
Carpentier, J.; Mortreux, A. Chem. Rev. 1995, 95, 2485;
(d) Gladiali, S.; Bayo¨n, J. C.; Claver, C. Tetrahedron:
Asymmetry 1995, 6, 1453; (e) Breit, B.; Seiche, W.
Synthesis 2001, 1; (f) Claver, C.; van Leeuwen, P. W. N.
M. In Rhodium Catalyzed Hydroformylation; Claven, C.,
van Leeuwen, P. W. N. M., Eds.; Kluwer Academic
Publishers: Dordrecht, The Netherlands, 2000.
b Conversion was based on 1H NMR.
c Branched/linear ratio. Determined based on 1H NMR.
d Determined by GC analysis (Supelco’s Beta Dex 225). The absolute
configuration (S) was assigned by comparing the optical rotation of
the product with (S)-1-fomylethyl acetate.
Table 2. Asymmetric hydroformylation of vinyl acetate with Rh–L2
catalysta
2. (a) Babin, J. E.; Whiteker, G. T. Patent WO 9303839,
1992; (b) Sakai, N.; Mano, S.; Nozaki, K.; Takaya, H. J.
Am. Chem. Soc. 1993, 115, 7033; (c) Nozaki, K.; Sakai, N.;
Nanno, T.; Higashijima, T.; Mano, S.; Horiuchi, T.;
Takaya, H. J. Am. Chem. Soc. 1997, 119, 4413; (d)
Breeden, S.; Cole-Hamilton, D. J.; Foster, D. F.; Schwarz,
G. J.; Wills, M. Angew. Chem., Int. Ed. 2000, 39, 4106; (e)
Dieguez, M.; Pamies, O.; Ruiz, A.; Castillon, S.; Claver,
C. Chem. Eur. J. 2001, 7, 3086; (f) Cobley, C. J.; Gardner,
K.; Klosin, J.; Praquin, C.; Hill, C.; Whiteker, G. T.;
Zanotti-Gerosa, A.; Petersen, J. L.; Abboud, K. A. J. Org.
Chem. 2004, 69, 4031; (g) Clark, T. P.; Landis, C. R.;
Freed, S. L.; Klosin, J.; Abboud, K. A. J. Am. Chem. Soc.
2005, 127, 5040; (h) Axtell, A. T.; Cobley, C. J.; Klosin, J.;
Whiteker, G. T.; Zanotti-Gerosa, A.; Abboud, K. A.
Angew. Chem., Int. Ed. 2005, 44, 5834; (i) Huang, J.;
Bunel, E.; Allgeier, A.; Tedrow, J.; Storz, T.; Preston, J.;
Correll, T.; Manley, D.; Soukup, T.; Jensen, R.; Syed, R.;
Moniz, G.; Larsen, R.; Martinelli, M.; Reider, P. Tetra-
hedron Lett. 2005, 46, 7831; (j) Yan, Y.; Zhang, X. J. Am.
Chem. Soc. 2006, 128, 7198.
CHO
Rh(acac)(CO)2 /ligand
*
OAc
OHC
+
OAc
OAc
CO/H2, toluene
Entry Ligand L/Rh T (°C) Time Conv. b/l
ee (%)
(h)
(%)
1
2
3
4
5
6
7
8
9
L2
L2
L2
L2
L2
L2
L2
L2
L3
L3
L3
L3
1:1
2:1
4:1
6:1
4:1
4:1
4:1
4:1
4:1
4:1
4:1
4:1
40
40
40
40
60
80
60
60
40
40
60
60
12
12
12
12
12
12
24
36
12
24
12
24
6
98/2 35(S)
98/2 69(S)
98/2 77(S)
98/2 77(S)
97/3 72(S)
98/2 56(S)
98/2 66(S)
98/2 41(S)
98/2 80(S)
98/2 75(S)
98/2 73(S)
98/2 69(S)
16
23
3
43
>99
80
98
9
10
11
12
45
69
98
3. Whiteker, G. T.; Briggs, J. R.; Babin, J. E.; Barner, B. A.
In Catalysis of Organic Reactions; Morrell, D. G., Ed.;
Marcel Dekker: New York, 2003; p 359.
a Reactions were carried out under 10 atom of H2 and CO. Substrate/
Rh = 1000.
4. Cobley, C. J.; Klosin, J.; Qin, C.; Whiteker, G. T. Org.
Lett. 2004, 6, 3277.
5. For recent reviews, see: (a) Brunel, J. M. Chem. Rev. 2005,
105, 857; (b) Kocovsky, P.; Vyskocyl, S.; Smrcina, M.
Chem. Rev. 2003, 103, 3213; (c) Chen, Y.; Yekta, S.;
Yudin, A. K. Chem. Rev. 2003, 103, 3155.
roformylation usually decreases rapidly with prolonged
reaction time due to product isomerization. This factor
was examined in detail with different reaction time rang-
ing from 12 h to 36 h. As shown in the table (Table 2,
entries 5 and 8), the enantioselectivity dropped from
72% ee (12 h) to only 41% ee (36 h), with an increased
conversion from 43% to 98%. Asymmetric hydroformy-
lation with ligand L3 was also investigated (Table 2, en-
tries 9–12). The best enantioselectivity (80% ee) was
achieved at 40 °C for 12 h, although the conversion
was only 9% (Table 2, entry 9). Elevated reaction tem-
perature and prolonged reaction time resulted in 98%
conversion with lower enantioselectivity (Table 2, entry
12).
´
`
6. Dieguez, M.; Pamies, O.; Claver, C. J. Org. Chem. 2005,
70, 3363.
7. (a) Anschutz, L.; Broeker, W.; Neher, R.; Ohnheiser, A.
¨
Chem. Ber. 1943, 76, 218; (b) Anschutz, L.; Marquardt,
¨
W. Chem. Ber. 1956, 89, 1119; (c) Billig, E.; Abatjoglou,
A. G.; Bryant, D. R. US. Patents 4,668,651 (1987) and
4,769,498 (1988); (d) Pastor, S. D.; Shum, S. P.; Rodeb-
augh, R. K.; Debellis, A. D.; Clarke, F. H. Helv. Chim.
Acta 1993, 76, 900.
8. (a) Cox, P. J.; Wang, W.; Snieckus, V. Tetrahedron Lett.
1992, 33, 2253; (b) Simonsen, K. B.; Gothelf, K. V.;
Jorgenson, K. A. J. Org. Chem. 1998, 63, 7536.
9. General procedure for synthesis of ligands L1–L4. To a
solution of 3b (438 mg, 1 mmol) in THF (15 mL) at 0 °C
was added dropwise n-BuLi (3 mmol, 1.2 mL of 2.5 M
hexane solution). The reaction mixture was allowed to
warm to room temperature and stirred for 30 min to give a
deep red solution. The reaction mixture was then recooled
In conclusion, four structural related diphosphite
ligands L1–L4 have been synthesized from readily avail-
able starting materials. Their application in asymmetric
hydroformylation reactions of vinyl acetate has been
investigated. Moderate enantioselectivities (up to 80%
ee) and excellent regioselectivities (b/l up to 98/2) have

4784
Y. Zou et al. / Tetrahedron Letters 48 (2007) 4781–4784
to 0 °C, and then was added dropwise to 2 (1.43 g,
125.22, 123.94, 35.27, 35.09, 34.59, 34.46, 31.63, 31.50,
31.28, 31.23, 31.20. 31P NMR (146 MHz, CD2Cl2): d
140.18 (s). ES+HRMS calcd for C88H101O6P2 [MH+]
1315.7073, found 1315.6960.
3 mmol) in THF (10 mL). After addition, the cooling bath
was removed and the mixture was stirred at room
temperature overnight. The volatiles were evaporated
under reduced pressure. To the residue was added CH2Cl2
(10 mL), and the mixture was filtered to remove the salt.
The filtration was concentrated and subjected to chroma-
tography on silica gel (eluted with hexane/EtOAc 25:1) to
afford pure ligands L2 722 mg (55% yield). Spectra data
for ligand L2: 1H NMR (360 MHz, CD2Cl2): d 8.04 (s,
2H), 7.85 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 7.9 Hz, 4H),
7.40–7.31 (m, 6H), 7.19–7.12 (m, 4H), 6.93 (t, J = 7.2 Hz,
2H), 6.84–6.77 (m, 8H), 1.31 (s, 18H), 1.16 (s, 18H), 1.14
(s, 18H), 1.00 (s, 18H). 13C NMR (126 MHz, CDCl3): d
146.34, 146.10, 145.80, 145.46, 140.10, 139.92, 137.94,
135.57, 134.39, 133.04, 132.26, 130.96, 130.26, 128.12,
127.82, 127.03, 126.98, 126.53, 126.38, 126.30, 126.24,
10. General procedure for asymmetric hydroformylation: To
a 2 mL vial equipped with a magnetic bar were added
ligand (0.004 mmol), Rh(acac)(CO)2 (0.001 mmol in
0.10 mL of toluene), and vinyl acetate (1.0 mmol), and
additional benzene was charged to bring the total volume
of the reaction mixture to 1.0 mL. Carbon monoxide
(10 atm) and dihydrogen (10 atm) were charged in
sequence. The reaction mixture was stirred (120 rpm) at
40 °C (oil bath) for 24 h. The conversion and regioselec-
tivity were determined by 1H NMR spectroscopy from the
crude reaction mixture. The enantiomeric excess was
determined directly by GC analysis of the crude reaction
mixture.