New modular P-chiral ligands for Rh-catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1016/j.tetlet.2006.10.122

New modular P-chiral ligands have been prepared from commercially available (S)-α,α-diphenylprolinol. With these new types of ligands, up to 95% ee was achieved in the Rh-catalyzed asymmetric hydrogenation of functionalized olefins.

Full text of DOI:10.1016/j.tetlet.2006.10.122

Tetrahedron Letters 47 (2006) 9013–9015
New modular P-chiral ligands for Rh-catalyzed
asymmetric hydrogenation
Oleg G. Bondarev* and Richard Goddard
Max-Planck-Institut fu¨r Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mu¨lheim an der Ruhr, Germany
Received 13 September 2006; revised 20 October 2006; accepted 24 October 2006
Abstract—New modular P-chiral ligands have been prepared from commercially available (S)-a,a-diphenylprolinol. With these new
types of ligands, up to 95% ee was achieved in the Rh-catalyzed asymmetric hydrogenation of functionalized olefins.
Ó 2006 Elsevier Ltd. All rights reserved.
Ph
We recently reported the synthesis and catalytic applica-
tion to asymmetric hydrogenation of P,P-bidentate
ligands derived from commercially available (S)-a,a-
diphenylprolinol.1 Recent catalytic results showing that
traditional chelating ligands are not necessary to achieve
a high enantioselectivity2 prompted us to develop
further analogous P-monodentate ligands.
Ph
Ph
Ph
H
PCl3
O
OH
P
N
N
H
Cl
1
2
Ph
3a R= CH3
b R= C2H5
c R= CH(CH3)2
d R= c-C6H11
e R= C(CH3)3
f R= C6H5
g R= 2,6-(CH3)2-C6H3
h R= 9-Fluorenyl
i R= CH2Ph
j R= (S)-CH(Ph)(CH3)
k R= (R)-CH(Ph)(CH3)
l R=
Ph
H
ROH
NEt3
O
P
In contrast to the extensive use of BINOL-based
monodentate chiral phosphites, phosphonites, and
phosphoramidites,3 little is known concerning similar
ligands based on other building blocks.4 The concept of
replacing the BINOL chiral scaffold with amino alcohols
leads to the design of new chiral ligands. The variable
environment of the phosphorus atom in such com-
pounds provides an excellent opportunity for facile
modular construction of structurally tunable ligands,
which can be considered as one of the advantages of this
class of ligands.
N
RO
O
O
OCH2Ph
Scheme 1.
In this letter, we describe the synthesis of (S)-a,a-diphen-
ylprolinol derived P-chiral monodentate ligands and
some preliminary results of their application in Rh-cat-
alyzed asymmetric hydrogenation.
for the preparation of phosphonite ligands 3m–t is the
treatment of with chlorophosphines RPCl2 as
phosphorylating agent (Scheme 2).2d,7 Monodentate
1
Synthesis of ligands involves diastereoselective phos-
phorylation of 1 by PCl3 with an exclusive formation
of (S,RP)-25 followed by the standard phosphorylation
of alcohols (Scheme 1).6 An alternative procedure used
3m R= CH3
n R= C2H5
Ph
Ph
Ph
Ph
H
RPCl2
NEt3
O
o R=C3H7
OH
p R= CH(CH3)2
r R= c-C6H11
s R= C(CH3)3
t R= C6H5
P
N
H
N
R
Keywords: Asymmetric reactions; Phosphorus ligands; Rhodium;
Hydrogenation.
1
*
Corresponding author. Tel.: +49 208 306 2000; fax: +49 208 306
2985; e-mail: bondarev@mpi-muelheim.mpg.de
Scheme 2.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.122

9014
O. G. Bondarev, R. Goddard / Tetrahedron Letters 47 (2006) 9013–9015
phosphoramidite derivatives 3u–v were prepared by
reacting 1 with hexamethyl- and ethylphosphorustri-
amide in refluxing toluene (Scheme 3).2e,8
Ph
NHAc
H2
Ph
NHAc
*
CO2CH3
CO2CH3
[Rh(COD)2]BF4/L
H2
5
4
NHAc
CO2CH3
6
NHAc
Ph
*
Ph
Ph
H
Ph
P(NMe2)3 or P(NEt2)3
O
P
CO2CH3
3u R= CH3
v R= C2H5
[Rh(COD)2]BF4/L
OH
N
N
H
Toluene
R2N
7
CO2CH3
H2
CO2CH3
1
*
CO2CH3
CO2CH3
Scheme 3.
[Rh(COD)2]BF4/L
8
9
An X-ray analysis of 3g9 was performed in order to con-
firm its structure and determine absolute configuration
at the phosphorus atom (Fig. 1). According to the X-
ray diffraction data, the ligand has an expected pseudo-
equatorial orientation of the exocyclic substituent at the
phosphorus atom (i.e., S configuration at the P-stereo-
center).
Scheme 4.
Table 1. Rh-catalyzed olefin-hydrogenationa
Entry
Ligand
ee of 5
ee of 7
ee of 9
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
3a
3b
3c
3d
3e
3f
78 (S)
84.6 (S)
91 (S)
69.4 (S)
74.6 (S)
71 (S)
77.2 (S)
21.8 (S)
43.4 (S)
88.3 (S)
25 (S)
73.2 (S)
91.3 (S)
88 (S)
90.2 (R)
87 (R)
84.3 (R)
62.4 (R)
53.3 (R)
62 (R)
18.8 (R)
32.8 (R)
84 (R)
87.2 (S)
63.2 (S)
67.8 (S)
54.4 (S)
76.2 (S)
25.4 (S)
60.6 (S)
87.4 (S)
21.8 (S)
76.2 (S)
91.8 (S)
95.2 (S)
91.7 (S)
87.6 (S)
43b (S)
3g
3h
3i
3j
32.8 (R)
87.3 (R)
94.5 (R)
60.4 (R)
65.5 (R)
60.6 (R)
24.2d(R)
16.2g (R)
3k
3l
3m
3n
3o
3p
3r
3s
3t
83.7 (S)
76.8 (S)
71.6c (S)
69.2f (S)
35.8e (S)
35h (S)
80.7 (S)
88.4 (S)
47.6k (S)
i
j
—
—
71.8 (S)
91.1 (S)
59l (S)
62 (R)
61 (R)
44.4m (R)
3u
3v
a Rh/substrate ratio 1:1000, CH2Cl2, 1.3 bar H2, 20 °C, 20 h, conver-
sion: 100%.
b Conversion: 85%.
c Conversion: 72%.
d Conversion: 64%.
e Conversion: 58%.
f Conversion: 68%.
Figure 1. X-ray crystal structure of 3g.
g Conversion: 38%.
h Conversion: 10%.
i Conversion: 3%.
The new ligands were efficiently applied in the Rh-cata-
lyzed hydrogenation of common benchmark substrates,
namely, methyl a-acetylaminocinnamate 4, methyl a-
acetamidoacrylate 6, and dimethyl itaconate 8 (Scheme
4). In all cases the cationic rhodium catalyst was pre-
pared in situ by treating [Rh(cod)2]BF4 with 2 equiv of
the corresponding monodentate ligand in CH2Cl2.
j Conversion: 2%.
k Conversion: 78%.
l Conversion: 79%.
m Conversion: 49%.
The configuration at R-substituent plays a very impor-
tant role. (R,S,SP)-3k represents a matched (entry 11)
case versus mismatched case (S,S,SP)-3j (entry 10).
The best results were shown by ligand 3l (entry 12,
91–95% ee) prepared from 1,4:3,6-dianhydro-D-manni-
tol. From entries 1, 13, 20 it becomes evident that the
nature of phosphorus atom (phosphites, phosphonites,
and phosphoramidites) has a pronounced influence on
the enantioselectivity in hydrogenation. The results
The results summarized in Table 1 show that the degree
of enantioselectivity strongly depends on the nature of
the R-group in the ligands. Increasing of the substituent
R steric demands by changing methyl and ethyl groups
to bulkier ones led to a sharp decrease of enantioselec-
tivity (entry 1 and 2 vs 3–5; entry 13 and 14 vs 15–18;
entry 20 vs 21).

O. G. Bondarev, R. Goddard / Tetrahedron Letters 47 (2006) 9013–9015
9015
Zhang, W.; Zhang, Z.; Zhang, X. Org. Lett. 2004, 6, 3565–
3567; Liu, Y.; Ding, K. J. Am. Chem. Soc. 2005, 127,
10488–10489.
obtained in the asymmetric hydrogenation of dimethyl
itaconate followed the same trend as those for methyl
a-acetamidoacrylate and methyl a-acetylaminocinna-
mate, but the enantioselectivity for phosphonites 3m–t
and phosphoramidites 3u–v were somewhat lower.
5. (a) Kranich, R.; Eis, K.; Geis, O.; Muhle, S.; Bats, J. W.;
¨
Schmalz, H.-G. Chem. Eur. J. 2000, 6, 2874–2894;
(b) Blume, F.; Zemolka, S.; Fey, T.; Kranich, R.; Schmalz,
H.-G. Adv. Synth. Catal. 2002, 344, 868–883.
In summary, new modular P-chiral ligands derived from
(S)-a,a-diphenylprolinol have been synthesized for the
first time. The new ligands have demonstrated a high
enantioselectivity in the Rh-catalyzed hydrogenation of
methyl a-acetamidoacrylate (up to 91% ee), methyl a-
acetylaminocinnamate (up to 95% ee), and dimethyl
itaconate (up to 95% ee). Also, we have taken the advan-
tage of these highly modular ligands to show that cata-
lyst optimization can be done easily by variation of the
substituent attached to the phosphorus atom.
6. General procedure for the preparation of ligands 3a–l: The
appropriate alcohol (5.4 mmol) was added at À78 °C to
stirred solution of reagent 2 (1.7 g, 5.4 mmol) and Et3N
(0.73 mL, 5.4 mmol) in ether (30 mL). The reaction mixture
was warmed to rt and stirred for 10 h. Then the solution
was filtered and the solvent evaporated in vacuum. The
residue was dried in vacuum to give the desired product.
Yield: 86–92%. Spectral data of 3a: 31P NMR (121.5 MHz,
CD2Cl2): d 141.1; 1H NMR (300 MHz, CD2Cl2): d 7.42 (m,
2H), 7.25–7.28 (m, 2H), 7.06–7.20 (m, 6H), 4.33 (dd,
J = 7.7, 3.6 Hz, 1H), 3.31 (m, 1H), 3.01 (d, J = 9.0 Hz, 3H),
2.91 (m, 1H), 1.73 (m, 1H), 1.40 (m, 2H), 0.77 (m, 1H); 13
C
NMR (75.5 MHz, CD2Cl2): d 144.2, 142.0, 127.3, 126.9,
126.5, 126.3, 126.2, 125.9, 94.1 (d, J = 12.4 Hz), 69.8 (d,
J = 2.5 Hz), 48.2, 45.3 (d, J = 32.2 Hz), 28.4, 24.9 (d,
J = 3.3 Hz). MS (EI), m/z (I, %): 313 (41) [M]+. Anal.
Calcd for C18H20NO2P: C, 69.00; H, 6.43; N, 4.47. Found:
C, 69.22; H, 6.68; N, 4.24.
Acknowledgements
O.G.B. thanks the Alexander von Humboldt-Stiftung
for a research fellowship. The authors thank Professor
M. T. Reetz for helpful discussions.
7. (a) Tani, K.; Yamagata, T.; Nagata, K. Acta Crystallogr.,
Sect. C 1994, 50, 1274–1276; (b) General procedure for the
preparation of ligands 3m–t: (S)-a,a-diphenylprolinol 1
(0.885 g, 3.5 mmol) was added at À78 °C to stirred solution
of phosphorylating reagent RPCl2 (3.5 mmol) and Et3N
(0.72 mL, 7 mmol) in ether (25 mL). The reaction mixture
was warmed to rt, stirred for 10 h. The solution was filtered,
the solvent was evaporated in vacuum, and the residue was
dried in vacuum. Yield: 89–95%. Spectral data of 3n: 31P
NMR (121.5 MHz, CD2Cl2): d 169.7; 1H NMR (300 MHz,
CD2Cl2): d 7.40 (dt, J = 8.6, 1.5 Hz, 2H), 7.02–7.31 (m,
8H), 4.32 (dd, J = 7.5, 2.9 Hz, 1H), 3.08 (m, 2H), 1.91 (m,
1H), 1.59 (m, 1H), 1.38 (m, 1H), 0.94–1.16 (m, 3H), 0.74
(dt, J = 13.6, 7.6 Hz, 3H); 13C NMR (75.5 MHz, CD2Cl2):
d 146.2, 143.4, 127.3, 126.7, 126.4, 126.2, 126.0, 125.8, 91.4
(d, J = 11.7 Hz), 70.3 (d, J = 3.5 Hz), 52.7 (d, J = 26.6 Hz),
28.8 (d, J = 25.2 Hz), 28.5, 24.4, 24.4 (d, J = 16.9 Hz).
HRMS (ESI): Calcd m/z 312.151422 (C19H22NOP+H).
Found m/z 312.151178.
8. (a) Delapierre, G.; Brunel, J. M.; Constantieux, T.; Buono,
G. Tetrahedron: Asymmetry 2001, 12, 1345–1352; (b)
General procedure for the preparation of ligands 3u–v: A
solution of 1 (0.759 g, 3 mmol) with P(NMe2)3 or P(NEt2)3
(3 mmol) in toluene (10 mL) was heated to reflux for 12 h.
After cooling to rt, the solvent was evaporated in vacuum,
and the residue was dried in a high vacuum. Yields: 96–
98%. The spectral data of 3u: 31P NMR (121.5 MHz,
CDCl3): d 145.1; 13C NMR (75.5 MHz, CDCl3): d 144.9,
142.8, 127.0, 126.5, 126.1, 125.9, 125.8, 125.5, 91.6 (d,
J = 12.3 Hz), 69.0, 46.7 (d, J = 35.3 Hz), 34.8 (d,
J = 17.5 Hz), 28.5, 24.3 (d, J = 3.4 Hz). HRMS (ESI):
Calcd m/z 327.161916 (C19H23N2OP+H). Found m/z
327.162076.
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9. Crystal data: (S,SP)-3g: C25H26NO2P, M = 403.44, mono-
clinic, space group P21 (No. 4), a = 8.5828(12), b =
3
˚
˚
10.3342(15), c = 13.3894(9) A, U = 1054.1(2) A , Z = 2,
l = 1.314 mmÀ1
0.0420. CCDC 620477.
, T = 100 K, 3122 unique data, R1 =