Evaluation of calix[4]arene-based chiral diphosphite ligands in Rh-catalyzed asymmetric hydrogenation of simple dehydroamino acid derivatives

Article abstract of DOI:10.1016/j.molcata.2010.03.034

The versatile calix[4]arene framework yielded chiral diphosphite ligands applicable for Rh-catalyzed asymmetric hydrogenation of dehydroamino acid derivatives. Optimum efficiency was obtained for: R¹ =-C(CH ₃)₃; R²

Full text of DOI:10.1016/j.molcata.2010.03.034

Journal of Molecular Catalysis A: Chemical 325 (2010) 65–72
Contents lists available at ScienceDirect
Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
Evaluation of calix[4]arene-based chiral diphosphite ligands in Rh-catalyzed
asymmetric hydrogenation of simple dehydroamino acid derivatives
Shasha Liua, Christian A. Sandovalb,∗
a Department of Chemistry, College of Science, Tianjin University, 92 Weijin Rd, Tianjin 300072, PR China
b Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Rd, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The calix[4]arene framework was readily modified to generate a number of chiral BINOL-based diphos-
phite ligands (3) capable of forming in situ Rh-complexes which catalyzed the asymmetric hydrogenation
of model substrates methyl-(Z)-2-(acetamido)acrylate (1a) and methyl-(Z)-2-(acetamido)cinnamate
(1b). The (S,S)-catalyst generated the (R)-product. Upper rim (R1) and 1,3-O-alkylation (R2) substitu-
tion on the calixarene strongly influenced catalyst activity and chiral induction. Optimum results were
obtained when R1 was –C(CH3)3 and R2 was –CH2CH2CH3 (3b). Under optimized conditions, 3b hydro-
genated 1a and 1b in 98 and 96% ee, respectively. Overall, better catalyst performance was observed for
“locked” cone-conformers of 3, with higher activity evident for the less sterically hindered 1a (TOF up to
1300 h−1 at P(H2) = 5 atm).
Received 2 December 2009
Received in revised form 4 March 2010
Accepted 29 March 2010
Available online 3 April 2010
Keywords:
Asymmetric catalysis
Homogeneous catalysis
Hydrogenation
Calixarene
© 2010 Elsevier B.V. All rights reserved.
Phosphite ligand
Rhodium
1. Introduction
found to promote formation of the desired linear aldehyde prod-
uct [9]. By comparison, the use of calixarene-based P-ligands for
Asymmetric hydrogenation of prochiral olefins by transition
metal molecular catalysts are among the most important and
widely used catalytic transformations [1]. The ability to generate
chiral compounds efficiently using molecular hydrogen has further
led to the development of several industrial applications [1,2]. Due
to the ubiquitous role of chiral phosphine ligands in such systems,
and the current growing demand for optically pure compounds, the
further development of novel chiral phosphine and other P-based
ligands is of great interest [1,3]. Among the variety of P-linkages
(P–C (aromatic or aliphatic), P–O, P–N) that have been used for lig-
and construction [1c,3,4], phosphite-based ligands have proven to
be a cost effective and versatile structural and functional motif [5,6].
Here, BINOL (BINOL = 2,2ꢀ-dihydroxy-1,1ꢀ-binaphthyl) based phos-
phites have generally yielded the most effective catalysts giving
hydrogenation products in (often) very high enantiomeric purity.
Calixarenes are a readily modified macrocyclic family that have
served as appropriate platforms for the construction of P-ligands
for a range of catalytic transformations [7–9]. For phosphite-based
calixarenes, application in hydroformylation catalysis has been
particularly successful due to the inherently large bite angles
such P-ligands form with the central metal [10], which has been
related asymmetric hydrogenation has remained relatively unex-
plored [11,12]. Herein, we describe the application of several chiral
diphosphite calixarene-based ligands in Rh-catalyzed asymmetric
hydrogenation and evaluate their potential using methyl-(Z)-2-
(acetamido)acrylate (1a) and methyl-(Z)-2-(acetamido)cinnamate
(1b) as model substrates.
2. Experimental
2.1. Materials and methods
All moisture and oxygen sensitive manipulations were per-
formed using standard Schlenk techniques under an argon
atmosphere. Toluene, ether and THF were freshly distilled from
metal sodium/benzophenone under argon prior to use. CH2Cl2
was freshly distilled from CaH2 under argon prior to use. CH3OH,
(CH3)2CHOH, (CH3)3COH, CH3CO2CH2CH3 and CH2ClCH2Cl were
distilled from CaH2 and stored under argon. CDCl3 was stored
under CaH2 and collected by cold distillation under vacuum
prior to use. Solvents used in the hydrogenation reactions were
degassed by three freeze-and-thaw cycles prior to use. Triethy-
lamine and phosphorus trichloride were distilled form CaH2 under
argon. Other commercially available materials were used with-
out further purification. Hydrogen gas (99.9999%) was obtained
from Shanghai Fujiang Specialty Gases Co., Ltd. [Rh(COD)2BF4]2
∗
Corresponding author. Tel.: +86 21 5492 5312; fax: +86 21 5492 5480.
E-mail address: sandoval@mail.sioc.ac.cn (C.A. Sandoval).
1381-1169/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.molcata.2010.03.034

66
S. Liu, C.A. Sandoval / Journal of Molecular Catalysis A: Chemical 325 (2010) 65–72
(d, 4J = 2.4 Hz, 2 H, calix-ArH), 6.82 (d, 4J = 2.4 Hz, 2 H, calix-ArH),
6.74 (d, 4J = 2.4 Hz, 2 H, calix-ArH), 6.62 (d, 4J = 2.4 Hz, 2 H, calix-
ArH), 4.74 and 3.39 (AB system, 2J = 12.9 Hz, 4 H, ArCH2Ar), 4.65
and 2.95 (AB system, 2J = 12.9 Hz, 4 H, ArCH2Ar), 3.70–3.63 (m, 4
H, OCH2), 1.81–1.63 (m, 4 H, OCH2CH2), 1.10 (s, 18 H, C(CH3)3),
1.08 (s, 18 H, C(CH3)3), 0.29 (t, 3J = 7.8 Hz, 6 H, CH2CH3); 31P NMR
(162 MHz, CDCl3) ı = 137.20 (s, trace), 136.99 (s, trace), 135.87 (s),
133.00 (br s, major, cone conformational isomer), 132.86 (s), 132.48
(s, trace), 127.25 (s), 120.85 (s). Note that 3b was obtained pre-
dominantly as the cone-conformer (ca. 90%) and was used without
further separation for hydrogenation experiments.
[13], methyl-(Z)-2-(acetamido)acrylate (1a) [14], methyl-(Z)-2-
(acetamido)cinnamate (1b) [15], p-tert-butylcalix[4]arene [16],
calix[4]arene [17] and p-benzylcalix[4]arene [18] were synthesized
according to reported procedures. 1H-, 13C- and 31P NMR data were
collected on a Varian Mercury vx 300 or 400 spectrometer. Chem-
ical shifts are expressed in parts per million (ppm) relative to TMS
(1H), CHCl3 residue (13C) or 85% H3PO4 31P). MS (MALDI) were
(
recorded on a IonSpec 4.7 (Applied IonSpec Co.). Elemental analyses
were performed on an Elementar vario EL III. Gas chromatogra-
phy (GC) analysis was conducted on an Agilent Technologies 7890A
instrument equipped with a Chirasil-DEX CB fused silica capillary
column (df = 0.25 ␮m, 0.25 mm i.d., 25 m, Varian). High perfor-
mance liquid chromatography (HPLC) analysis was conducted on
a Waters 515 instrument equipped with a Chiralpak AD-H column
(0.46 cm i.d., 25 cm L, Daicel). Optical rotations were obtained using
a Jasco P-1030 polarimeter.
2.2.3. (S,S)-5,11,17,23-Tetra-tert-butyl-25,27-dibutoxy-26,28-
bis(1,1ꢀ-binaphthyl-2,2ꢀ-dioxyphosphanyloxy)calix[4]arene
(3c)
A suspension of p-tert-butyl-1,3-dibutoxycalix[4]arene [22]
(931 mg, 1.22 mmol) and NaH (122 mg, 60% dispension in oil,
3.05 mmol) in dried toluene (30 mL) was heated under reflux
for 18 h. [(S)-(1,1ꢀ-Binaphthalene-2,2ꢀ-diyl)]chlorophosphite [20]
(941 mg, 2.68 mmol) in dried toluene (15 mL) was added at 0 ◦C and
the reaction mixture was stirred for 2 h at RT. The crude reaction
mixture was filtered through a short pad of silica gel and washed
with toluene (3× 15 mL). The filtrate was concentrated to ca. 5 mL.
Addition of petroleum ether (50 mL) gave the title compound as
colorless crystals (873 mg, 52%): 1H NMR (300 MHz, CDCl3) ı = 7.88
(d, 3J = 8.1 Hz, 4 H, BINOL-ArH), 7.76 (d, 3J = 8.1 Hz, 2 H, BINOL-ArH),
7.70 (d, 3J = 9.0 Hz, 2 H, BINOL-ArH), 7.47 (d, 3J = 9.0 Hz, 2 H, BINOL-
ArH), 7.42–7.10 (m, 14 H, BINOL-ArH), 7.02–6.97 (m, 4 H, calix-ArH),
6.73 (d, 4J = 1.8 Hz, 2 H, calix-ArH), 6.56 (d, 4J = 1.8 Hz, 2 H, calix-
ArH), 4.62 and 3.37 (AB system, 2J = 12.9 Hz, 4 H, ArCH2Ar), 4.62
and 3.11 (AB system, 2J = 12.9 Hz, 4 H, ArCH2Ar), 3.64–3.44 (m, 4 H,
OCH2), 1.73–1.65 (m, 4 H, OCH2CH2), 1.24 (s, 18 H, C(CH3)3), 0.99
(s, 18 H, C(CH3)3), 0.90–0.82 (m, 4 H, CH2CH3), 0.20 (t, 3J = 6.6 Hz,
6 H, CH2CH3); 13C NMR (100.5 MHz, CDCl3) ı = 154.18–121.90
(Ar–C), 75.51 (s, OCH2), 33.96 (s, C(CH3)3), 33.75 (s, C(CH3)3),
32.46 (s, ArCH2Ar), 31.83 (s, ArCH2Ar), 31.60 (s, C(CH3)3), 31.32 (s,
OCH2CH2), 31.28 (s, C(CH3)3), 18.35 (s, CH2CH3), 13.82 (s, CH2CH3);
31P NMR (121.5 MHz, CDCl3) ı = 140.77 (br s, P(OAr)3). MS (MALDI):
m/e 1411.6 [M+Na]+. Anal. Calcd. for C92H94O8P2 (1389.67): C,
79.51; H, 6.82; found: C, 79.68; H, 6.92. Only the cone-conformer
for 3c was obtained. Crystals of 3c (colorless) suitable for X-ray
diffraction were obtained by slow diffusion of petroleum ether into
a solution of 3c in toluene.
2.2. Synthesis of compounds
2.2.1. (S,S)-5,11,17,23-Tetra-tert-butyl-25,27-dimethoxy-26,28-
bis(1,1ꢀ-binaphthyl-2,2ꢀ-dioxyphosphanyloxy)calix[4]arene
(3a)
A hexane solution of n-BuLi (0.75 mL, 2.5 mol/L, 1.86 mmol)
was slowly added at 0 ◦C to
a stirred solution of p-tert-
butyl-1,3-dimethoxycalix[4]arene [19] (630 mg, 0.93 mmol) in
dried THF (30 mL) using a syringe. The reaction mixture was
stirred for 2 h at RT. Subsequently, [(S)-(1,1ꢀ-binaphthalene-2,2ꢀ-
diyl)]chlorophosphite [20] (652 mg, 1.86 mmol) in dried THF (8 mL)
was added at 0 ◦C and the reaction mixture was stirred for 11 h at
RT. After removal of the volatiles, 25 mL of CH2Cl2 was added to the
resulting solid. LiCl was removed by filtration through a short pad
of Celite and the filtrate was evaporated to dryness. The residue was
subjected to flash chromatography (eluent: petroleum ether/ethyl
acetate = 200/1) to afford the title compound (622 mg, 51%) as a
white foamy solid: 1H NMR (300 MHz, CDCl3) ı = 7.98–6.34 (m,
32 H, calix-ArH and BINOL-ArH), 4.54–3.01 (m, 14 H, ArCH2Ar
and OCH3), 1.33–0.72 (m, 36 H, C(CH3)3); 13C NMR (100.5 MHz,
CDCl3) ı = 156.08–120.81 (Ar–C), 60.75, 60.08, 57.86 (s, OCH3),
37.80 (s, ArCH2Ar), 37.13 (s, ArCH2Ar), 34.12 (s, C(CH3)3), 33.65 (s,
C(CH3)3), 32.43 (s, ArCH2Ar), 32.15 (s, ArCH2Ar), 31.65, 31.31, 31.02,
30.83, 29.70 (s, C(CH3)3); 31P NMR (121.5 MHz, CDCl3) ı = 145.99
(s, trace), 144.34 (s, trace), 143.99 (s, major), 142.31 (s), 138.18
(s). MS (MALDI): m/e 1305.6 [M+H]+; 1327.5 [M+Na]+. Anal. Calcd.
for C86H82O8P2 (1305.51): C, 79.12; H, 6.33; found: C, 78.01; H,
6.58. Note that 3a was obtained as a mixture of conformational iso-
mers which was used without further separation for hydrogenation
experiments.
2.2.4. (S,S)-5,11,17,23-Tetra-tert-butyl-25,27-dibenzyloxy-
26,28-bis(1,1ꢀ-binaphthyl-2,2ꢀ-dioxyphosphanyloxy)calix[4]arene
[9j] (3d)
2.2.2. (S,S)-5,11,17,23-Tetra-tert-butyl-25,27-dipropoxy-26,28-
bis(1,1ꢀ-binaphthyl-2,2ꢀ-dioxyphosphanyloxy)calix[4]arene [9i]
(3b)
A hexane solution of n-BuLi (0.8 mL, 2.5 mol/L, 2.0 mmol)
was slowly added at 0 ◦C to
a stirred solution of p-tert-
butyl-1,3-dibenzyloxycalix[4]arene [23] (828 mg, 1.0 mmol) in
dried THF (30 mL) using a syringe. The reaction mixture was
stirred for 2 h at RT. Subsequently, [(S)-(1,1ꢀ-binaphthalene-2,2ꢀ-
diyl)]chlorophosphite [20] (701 mg, 2.0 mmol) in dried THF (10 mL)
was added at 0 ◦C and the reaction mixture was stirred for 12 h
at RT. After removal of the volatiles, 30 mL of CH2Cl2 was added
to the resulting solid. LiCl was removed by filtration through a
short pad of Celite and the filtrate was evaporated to dryness.
The remaining residue was subjected to flash chromatography
(eluent: petroleum ether/ethyl acetate = 200/1) to afford the title
compound (450 mg, 31%) as a white solid: 1H NMR (300 MHz,
CDCl3) ı = 7.94 (d, 3J = 8.1 Hz, 2 H, BINOL-ArH), 7.71 (d, 3J = 8.7 Hz,
4 H, Bn-ArH), 7.50–7.44 (m, 2 H, Bn-ArH), 7.40–7.05 (m, 26 H, Bn-
ArH and BINOL-ArH), 6.69 (d, 4J = 2.4 Hz, 2 H, calix-ArH), 6.62 (d,
4J = 9.3 Hz, 2 H, calix-ArH), 6.44 (d, 4J = 2.4 Hz, 2 H, calix-ArH), 6.35
(d, 4J = 2.4 Hz, 2 H, calix-ArH), 5.11 (2J = 11.7 Hz, 2 H, CHHPh), 4.78
A suspension of p-tert-butyl-1,3-dipropoxycalix[4]arene [21]
(733 mg, 1.0 mmol) and NaH (119 mg, 60% dispension in oil,
2.98 mmol) in dried toluene (20 mL) was heated under reflux
for 17 h. [(S)-(1,1ꢀ-Binaphthalene-2,2ꢀ-diyl)]chlorophosphite [20]
(772 mg, 2.2 mmol) in dried toluene (10 mL) was added at 0 ◦C and
the reaction mixture was stirred for 2 h at RT. The crude reaction
mixture was filtered through a short pad of silica gel and washed
with toluene (2× 15 mL). The filtrate was concentrated to dry-
ness and the residue subjected to flash chromatography (eluent:
petroleum ether/ethyl acetate = 90/1) to afford the title compound
(454 mg, 33%) as a white foamy solid: 1H NMR (300 MHz, CDCl3)
ı = 7.93 (d, 3J = 8.1 Hz, 2 H, BINOL-ArH), 7.86 (d, 3J = 8.7 Hz, 2 H,
BINOL-ArH), 7.77 (d, 3J = 8.1 Hz, 2 H, BINOL-ArH), 7.59 (d, 3J = 8.7 Hz,
2 H, BINOL-ArH), 7.49 (d, 3J = 8.7 Hz, 2 H, BINOL-ArH), 7.46–7.09
(m, 12 H, BINOL-ArH), 7.04 (d, 3J = 8.7 Hz, 2 H, BINOL-ArH), 6.89

S. Liu, C.A. Sandoval / Journal of Molecular Catalysis A: Chemical 325 (2010) 65–72
67
(2J = 11.7 Hz, 2 H, CHHPh), 4.71 and 3.01 (AB system, 2J = 12.9 Hz, 4
H, ArCH2Ar), 4.71 and 2.60 (AB system, 2J = 12.9 Hz, 4 H, ArCH2Ar),
1.25 (s, 18 H, C(CH3)3), 0.81 (s, 18 H, C(CH3)3); 31P NMR (121.5 MHz,
CDCl3) ı = 123.89 (s, P(OAr)3). Only the cone-conformer for 3d was
obtained.
2.2.7. (S,S)-5,11,17,23-Tetra-benzyl-25,27-dibenzyloxy-26,28-
bis(1,1ꢀ-binaphthyl-2,2ꢀ-dioxyphosphanyloxy)calix[4]arene
(3g)
A suspension of p-benzyl-1,3-dibenzyloxycalix[4]arene [18]
(93 mg, 0.096 mmol) and NaH (9.6 mg, 60% dispension in oil,
0.24 mmol) in dried toluene (7 mL) was heated under reflux for 11 h.
[(S)-(1,1ꢀ-Binaphthalene-2,2ꢀ-diyl)]chlorophosphite [20] (67.7 mg,
0.193 mmol) in dried toluene (3 mL) was added at 0 ◦C and the
reaction mixture was stirred for 2 h at RT. The crude reaction mix-
ture was filtered through a short pad of silica gel and washed
with toluene (2× 5 mL). The filtered solution was evaporated to
dryness, leading to the title compound as a pale yellow foamy
solid (90.0 mg, 59%): 1H NMR (400 MHz, CDCl3) ı = 8.00–7.81 (m,
4H, BINOL-ArH), 7.61–7.59 (m, 4H, Bn-ArH), 7.38–7.10 (m, 42H,
BINOL-ArH and Bn-ArH), 6.96 (d, 3J = 3.6 Hz, 4H, Bn-ArH), 6.81
(s, 4H, calix-ArH), 6.67 (s, 4H, calix-ArH), 4.99 (s, 4H, OCH2Ph),
4.23 (d, 2J = 13.2 Hz, 4 H, ArCH2Ar), 3.84 (s, 4H, ArCH2Ph), 3.58
(s, 4H, ArCH2Ph), 3.21 (d, 2J = 13.2 Hz, 4 H, ArCH2Ar); 13C NMR
(100.5 MHz, CDCl3) ı = 151.62–126.19 (Ar–C), 78.29 (s, OCH2Ph),
77.20 (s, OCH2Ph), 41.23 (s, ArCH2Ph), 40.94 (s, ArCH2Ph), 31.54 (s,
ArCH2Ar); 31P NMR (121.5 MHz, CDCl3) ı = 145.68 (s). MS (MALDI):
m/e 1593.6 [M+H]+. Anal. Calcd. for C110H82O8P2 (1593.77): C,
82.90; H, 5.19. Found: C, 82.53; H, 5.94. Only the cone-conformer
for 3g was obtained.
2.2.5. (S,S)-5,11,17,23-Tetra-tert-butyl-25,27-dibenzyloxy-
26,28-bis(1,1ꢀ-binaphthyl-3,3ꢀ-dimethyl-2,2ꢀ-
dioxyphosphanyloxy)calix[4]arene
(3e)
A suspension of p-tert-butyl-1,3-dibenzyloxycalix[4]arene [23]
(99.6 mg, 0.12 mmol) and NaH (15.2 mg, 60% dispension in oil,
0.38 mmol) in dried toluene (7 mL) was heated under reflux for 13 h.
[(S)-(1,1ꢀ-binaphthalene-3,3ꢀ-dimethyl-2,2ꢀ-diyl)]chlorophosphite
[24] (90.9 mg, 0.24 mmol) in dried toluene (3 mL) was added at
0 ◦C and the reaction mixture was stirred for 2 h at RT. The crude
reaction mixture was filtered through a short pad of silica gel
and washed with toluene (2× 5 mL). The filtered solution was
evaporated to dryness, leading to the title compound as a pale
yellow foamy solid (103.2 mg, 57%): 1H NMR (400 MHz, CDCl3)
ı = 7.81–7.52 (m, 10 H, Bn-ArH and BINOL-ArH), 7.36–7.31 (m, 10H,
Bn-ArH and BINOL-ArH), 7.20–7.07 (m, 10H, BINOL-ArH), 7.04 (s,
4H, calix-ArH), 6.79 (s, 4H, calix-ArH), 5.04 (s, 4H, OCH2Ph), 4.29
(d, 2J = 12.8 Hz, 4 H, ArCH2Ar), 3.27 (d, 2J = 12.8 Hz, 4 H, ArCH2Ar),
2.32–2.22 (m, 12 H, BINOL-ArCH3), 1.29 (s, 18 H, C(CH3)3), 0.95
(s, 18 H, C(CH3)3); 13C NMR (100.5 MHz, CDCl3) ı = 150.72–123.04
(Ar–C), 77.92 (s, OCH2Ph), 33.91 (s, C(CH3)3), 33.79 (s, C(CH3)3),
31.70 (s, C(CH3)3), 31.42 (s, ArCH2Ar), 30.99 (s, C(CH3)3), 29.69
(s, ArCH2Ar), 19.72, 18.20, 18.16, 17.51, 17.29, 16.93 (s, BINOL-
ArCH3); 31P NMR (121.5 MHz, CDCl3) ı = 142.97 (s, major), 141.05
(s), 138.69 (s). MS (MALDI): m/e 1513.7 [M+H]+. HRMS (MALDI):
Calcd. for [C102H99O8P2]+: 1513.681; found: 1513.680. Anal. Calcd.
for C102H98O8P2 (1513.81): C, 80.93; H, 6.53; found: C, 78.21;
H, 7.78. Note that 3e was obtained as a mixture of conforma-
tional isomers which was used without further separation for
hydrogenation experiments.
2.3. Solution studies
2.3.1. In situ [(3)Rh(COD)]BF4 formation
Accurately measured amounts of (S,S)-3 (11.0–15.2 mg,
10 ␮mol) were placed in a pre-oven-dried (120 ◦C) 10 mL Schlenk
and the atmosphere replaced with argon. Dried CDCl3 (1.0 mL) was
added to obtain a 10 mM solution. To this was added 1 equiv. of
[Rh(COD)2BF4] (4.1 mg, 10 ␮mol) and the mixture gently stirred for
30 min. 31P NMR (162 MHz, CDCl3) spectra of resulting solutions
were obtained after a 5 and 30 min period. Following removal of
volatiles under vacuum, MS (MALDI) spectra for resulting powders
were obtained. Complex, ı (ppm); m/e: (a) [(3a)Rh(COD)]BF4,
120.6 (d, JRh,P = 256 Hz, 95%), 117.5 (d, JP,P = 46 Hz, <5%), 113.6 (d,
JP,P = 46 Hz, <5%); 1407.5 [(3a)Rh]+; (b) [(3b)Rh(COD)]BF4, 120.6
(dd, JRh,P = 255 Hz, JP,P = 41 Hz, 5%), 119.9 (d, JRh,P = 255 Hz, 85%),
117.2 (dd, JRh,P = 265 Hz, JP,P = 43 Hz, 5%), 117.1 (d, JP,P = 47 Hz, <5%),
113.0 (d, JP,P = 47 Hz, <5%); 1463.5 [(3b)Rh]+; (c) [(3c)Rh(COD)]BF4,
120.2 (d, JRh,P = 255 Hz, 90%), 117.5 (d, JP,P = 47 Hz, <5%), 113.5
(d, JP,P = 47 Hz, <5%); 1491.5 [(3c)Rh]+; (d) [(3d)Rh(COD)]BF4,
119.5 (d, JRh,P = 257 Hz, 90%), 117.7 (d, JP,P = 46 Hz, <5%), 113.8 (d,
JP,P = 46 Hz, <5%); 1559.5 [(3d)Rh]+; (e) 3e, no complex formation
was observed; (f) 3f, no complex formation was observed.
2.2.6. (S,S)-25,27-Dimethoxy-26,28-bis(1,1ꢀ-binaphthyl-2,2ꢀ-
dioxyphosphanyloxy)calix[4]arene
(3f)
A hexane solution of n-BuLi (0.6 mL, 1.6 mol/L, 0.972 mmol)
was slowly added at 0 ◦C to
a
stirred solution of 1,3-
dimethoxycalix[4]arene [25] (220 mg, 0.486 mmol) in dried
toluene (20 mL), using syringe. The reaction mixture was
a
stirred for 2 h at RT. Subsequently, [(S)-(1,1ꢀ-binaphthalene-2,2ꢀ-
diyl)]chlorophosphite [20] (341 mg, 0.972 mmol) in dried toluene
(5 mL) was added at 0 ◦C and the reaction mixture was stirred
for 12 h at RT. Following removal of volatiles, 15 mL of CH2Cl2
was added to the resulting solid. LiCl was removed by filtration
through a short pad of Celite and the filtrate was evaporated to dry-
ness. The residue was subjected to flash chromatography (eluent:
petroleum ether/ethyl acetate = 20/1) to afford the title compound
(172 mg, 33%) as a white solid: 1H NMR (400 MHz in CDCl3)
ı = 8.16–7.24 (m, 24 H, BINOL-ArH), 7.16–6.25 (m, 12H, calix-ArH),
4.55–2.82 (m, 14 H, ArCH2Ar and OCH3); 13C NMR (100.5 MHz,
CDCl3) ı = 158.61–121.83 (Ar–C), 77.20, 60.96, 60.05, 58.92 (s,
OCH3), 36.37, 35.38, 31.70, 31.62, 30.29, 29.67 (s, ArCH2Ar); 31P
NMR (162 MHz, CDCl3) ı = 148.07 (s), 145.43 (s, major), 144.80
(s). MS (MALDI): m/e 1081.3 [M+H]+; 1103.3 [M+Na]+. HRMS
(MALDI): Calcd. for [C70H51O8P2]+: 1081.3054; found: 1081.3073.
Anal. Calcd. for C70H50O8P2·4H2O (1081.09 + 72.06): C, 72.91; H,
5.07. Found: C, 70.89; H, 4.76. Note that 3f was obtained as a mixture
of conformational isomers and was used without further separation
for hydrogenation experiments.
2.3.2. Evidence for in situ [(3a)Rh(1b)]BF4 generation
Accurately measured amounts of (S,S)-3 (13.1–14.6 mg,
10 ␮mol) were placed in a pre-oven-dried (120 ◦C) 10 mL Schlenk
and the atmosphere replaced with argon. Dried CDCl3 (1.0 mL)
was added to obtain a 10 mM solution. To this was added 1 equiv.
of [Rh(COD)2BF4] (4.1 mg, 10 ␮mol) and the mixture gently stirred
(15 min). The resulting solution was then stirred under an H2
atmosphere (1 atm) for 15 min. 31P NMR spectra were obtained
under argon atm using 0.5 mL. To the remaining 0.5 mL was added
an aliquot (0.5 mL) of 1b in CDCl3 (10 mM, 1 equiv./Rh) under
argon. The resulting mixture was gently stirred for 30 min and the
31P NMR spectrum obtained. (a) [(3a)Rh(CDCl3)2]BF4 not formed,
120.0 (d, JRh,P = 255 Hz, [(3)Rh(COD)]BF4); no detectable change
with addition of 1b. (b) In situ generated [(3b)Rh(CDCl3)2]BF4
not detected, 120.5 (dd, JRh,P = 255 Hz, JP,P = 41 Hz, 10%), 119.4
(d, JRh,P = 255 Hz, 15%), 117.5 (dd, JRh,P = 266 Hz, JP,P = 43 Hz,
10%), 112.8 (d, JP,P = 60 Hz, 20%), 107.7 (d, JP,P = 60 Hz, 20%),
−3.95 (s, 35%); with addition of 1b, 126.4 (dd, JRh,P = 245 Hz,

68
S. Liu, C.A. Sandoval / Journal of Molecular Catalysis A: Chemical 325 (2010) 65–72
Scheme 1. Synthesis of calix[4]arene-based diphosphite ligands (3).
JP,P = 91 Hz, 35%), 124.9 (dd, JRh,P = 246 Hz, JP,P = 91 Hz, 35%), 119.9
(dd, JRh,P = 262 Hz, JP,P = 40 Hz, 5%), 119.2 (d, JRh,P = 255 Hz, 10%),
117.2 (dd, JRh,P = 264 Hz, JP,P = 42 Hz, 5%), 113.9 (d, JP,P = 56 Hz, 5%),
109.1 (d, JP,P = 56 Hz, 5%). (c) In situ generated [(3c)Rh(CDCl3)2]BF4,
121.7 (d, JRh,P = 353 Hz, ca. 20%); with addition of 1b, 126.1 (dd,
JRh,P = 249 Hz, JP,P = 96 Hz, 30%), 124.7 (dd, JRh,P = 248 Hz, JP,P = 96 Hz,
30%); 121.5 (d, JRh,P = 354 Hz, 5%), 119.4 (d, JRh,P = 255 Hz, 25%).
(d) In situ generated [(3d)Rh(CDCl3)2]BF4, 122.8 (s, ca. 10%); no
significant change with addition of 1b.
(300 MHz, CDCl3) ı = 6.15 (brs, 1 H), 4.66–4.56 (m, 1 H), 3.76 (s,
3 H), 2.03 (s, 3 H), 1.41 (d, 3J = 7.2 Hz, 3 H); GC (Chirasil-DEX CB
column) P = 12.0 psi, T = 180 ◦C, tR of (S)-2a = 17.29 min, tR of (R)-
2a = 17.53 min; [␣]D25 = −9.6◦ (c 1, CHCl3) [Lit. [26] [␣]D25 = −9.2◦
(c 1, CHCl3) for (R)-enantiomer]. (R)-N-acetyl-3-phenylalanine
methyl ester (2b): 1H NMR (300 MHz, CDCl3) ı = 7.32–7.22 (m,
3 H), 7.10–7.08 (m, 2 H), 6.03 (d, 3J = 6.0 Hz, 1 H), 4.92–4.86
(m, 1 H), 3.73 (s, 3 H), 3.19–3.05 (m, 2 H), 1.99 (s, 3 H); HPLC
(Chiralcel AD-H 250 column) hexane:isopropanol = 90:10, flow
rate = 0.7 mL/min, UV detection at 214 nm, tR of (R)-2b = 10.48 min,
tR of (S)-2b = 15.21 min; [␣]D25 = −13.4◦ (c 1, MeOH) [Lit. [26]
[␣]D25 = −15.8◦ (c 1, MeOH) for (R)-enantiomer].
2.4. Hydrogenations
2.4.1. Typical procedure for [Rh(COD)2BF4]/3-catalyzed
asymmetric hydrogenation using (S,S)-3b is given
2.4.2. Hydrogenation profiles
Accurately weighed amounts of Rh(COD)2BF4 (1.2 mg, 3 ␮mol)
and (S,S)-3b (6.1 mg, 4.5 ␮mol) were placed in a pre-oven-dried
glass autoclave containing a magnetic stirring bar. The mixture
was placed under high vacuum for at least 20 min before purging
with Ar. Degassed CH2Cl2 (1 mL) was added, the solution stirred
for 2–5 min, and then a solution of prochiral olefin (1a, 128.8 mg,
0.9 mmol; 1b, 65.8 mg, 0.3 mmol) in 2 mL of degassed CH2Cl2 was
added under an Ar atmosphere. H2 was introduced under 3 atm
pressure with several quick release–fill cycles before being set to
5 atm pressure. The solution was vigorously stirred at 30 ◦C. Follow-
ing the designated reaction time, H2 was released and the volatiles
removed under vacuum. The residue was dissolved in ether and
passed through a short pad of silica gel. Following removal of the
solvent under vacuum, the conversion was determined by 1H NMR
analysis and the enantiomeric excess (ee%) value obtained by chi-
ral GC or HPLC. (R)-N-Acetylalanine methyl ester (2a): 1H NMR
Hydrogenations were conducted in a glass autoclave equipped
with a sampling needle connected to a three-way stop valve as
previously described [27]. This experimental set-up allowed for
samples to be taken from the reaction mixture under an H2 atmo-
sphere. Accurately weighed amounts of Rh(COD)2BF4 (typically
2.4 mg, 6 ␮mol) and (S,S)-3 (11.7–14.3 mg, 9 ␮mol) were placed
in the autoclave containing a magnetic stirring bar. The mixture
was placed under high vacuum for at least 20 min before purg-
ing with Ar. Degassed CH2Cl2 (2 mL) was added, the solution
stirred for 20 min, and then a solution of 1a (typically 257.6 mg,
1.8 mmol) or 1b (typically 131.5 mg, 0.6 mmol) in 4 mL of degassed
CH2Cl2 was added under an Ar atmosphere such that the desired
Rh: 3:1 ratio was obtained. If needed, the autoclave was placed
in a pre-warmed oil-bath set at the desired reaction tempera-
ture. H2 was introduced under 7 atm pressure with several quick
release–fill cycles before being set to 5 atm pressure. Stirring and

S. Liu, C.A. Sandoval / Journal of Molecular Catalysis A: Chemical 325 (2010) 65–72
69
Fig. 1. Crystal structure of calix[4]arene-based chiral diphosphite ligand 3c. Hydrogen atoms are omitted for clarity (C, black; O, red; P, purple). (For interpretation of the
references to color in this figure legend, the reader is referred to the web version of the article.)
timing (t = 0 min) were immediately commenced. Reaction sam-
ples were obtained (2 drops into an ether-filled GC sample tube)
at specified time-intervals (t), and the extent of substrate con-
sumption and ee of (R)-2 determined by GC or HPLC. Conditions:
[Rh(COD)2BF4] = 1.0 mM; [(S,S)-3] = 1.5 mM; [1a] = 0.3 M (S/C = 300)
or [1b] = 0.1 M (S/C = 100); P(H2) = 5 atm; T = 30 ◦C; VT = 6 mL, sol-
vent = CH2Cl2.
3.2. In situ generation of catalytically relevant complexes
Formation of Rh/3 complexes was monitored in situ by mix-
ing CDCl3 solutions of 3 (10 mM) with Rh(COD)2BF4 (1 equiv.). For
3a–d, 31P NMR spectra of resulting mixtures showed a predom-
inant doublet centered at ı 119.5–120.6 ppm (JRh,P = 255–257 Hz)
even after only 5 min. Similarly, two AB systems were observed
for the bridging diastereotopic methylene protons. Accordingly,
the calixarene-diphosphite ligands adopt a cone-configuration
3. Results and discussion
which chelates the Rh-metal resulting in
a (time averaged)
pseudo-C2 complex [29]. Resonances consistent with formation
of other complexes were only present in minor amounts (ca.
5%). Even highly flexible 3a gave a single isomer in 95% yield
(ı 120.6, d, JRh,P = 256 Hz). Importantly, MS spectra of result-
ing solids following removal of volatiles were consistent with
[(3a–d)Rh(COD)]BF4 formation ([(3a–d)Rh]+, 1407.5–1559.5 m/e).
For 3e and 3f, no complex formation was detected under the same
conditions.
3.1. Synthesis and structure of calix[4]arene-based bisphosphite
ligands (3)
The known BINOL-derived calix[4]arene-diphosphite ligands 3b
and 3d, and previously unreported 3a, 3c and 3e–g were pre-
pared following known calixarene alkylation and phosphorylation
methods, Scheme
1
[18–25]. Addition of (S)- or (R)-(1,1ꢀ-
binaphthalene-2,2ꢀ-diyl)chlorophosphite to appropriately distally
O-dialkylated calixarene precursors in the presence of a base (NaH
or n-BuLi) led to the desired diphosphites 3 in typically 30–60%
yields. More sterically hindered calixarenes were obtained pre-
dominantly as the cone-conformer while conformationally flexible
macrocycles resulted in a mixture of (undetermined) isomers. For
the former, 1H NMR spectra exhibited two distinct AB patterns for
the bridging diastereotopic methylene protons, consistent with C2-
symmetry, and a single (broadened) resonance in 31P NMR spectra
(ı 123.9–145.4 ppm). Diffusion of petroleum ether into a toluene
solution of 3c yielded appropriate crystals for solid-state struc-
tural elucidation [28]. As shown in Fig. 1, the calixarene framework
adopts a flattened cone structure whereby the less sterically hin-
dered O-butyl groups are pushed inwards towards the calixarene
axis in accordance with previously reported crystal structures for
closely related calix[4]arene diphosphites [9i,j].
Fig.
2
shows the 31P NMR spectrum for in situ formed
[(3c)Rh(COD)]+ following partial hydrogenation of COD (1 atm,
15 min) and addition of 1b (1 equiv.) [30]. The resonances centered
at 121.7 (d, JRh,P = 353 Hz) and 126.1 (dd, JRh,P = 249 Hz, JP,P = 96 Hz),
124.7 (dd, JRh,P = 248 Hz, JP,P = 96 Hz) are tentatively assigned as
[(3c)Rh(CDCl3)2]+ and [(3c)Rh(1b)]+, respectively [30]. Similarly,
the same procedure for [(3b)Rh(COD)]+ yielded [(3c)Rh(1b)]+
with resonances at 126.4 (dd, JRh,P = 245 Hz, JP,P = 91 Hz) and 124.9
(dd, JRh,P = 246 Hz, JP,P = 91 Hz). For [(3a)Rh(COD)]+ no hydrogena-
tion of COD was apparent after addition of H2 (15 or 60 min,
1 atm), while addition of 1b (1 or 5 equiv.) to in situ gen-
erated [(3d)Rh(CDCl3)2]+ did not generate the corresponding
[(3d)Rh(1b)]+ complex. Thus, the observed solution behavior of
Rh/3 complexes varied significantly depending on the R1- and R2-
substituents in 3.
Fig. 2. 31P NMR spectrum following partial hydrogenation of COD in [(3c)Rh(COD)]+ (1 atm, 15 min) and addition of 1b (1 equiv.).

70
S. Liu, C.A. Sandoval / Journal of Molecular Catalysis A: Chemical 325 (2010) 65–72
Scheme 2. Asymmetric hydrogenation of methyl-(Z)-2-(acetamido)acrylate (1a)
and methyl-(Z)-2-(acetamido)cinnamate (1b) catalyzed by in situ generated cat-
alysts comprised of [Rh(COD)2BF4] and calix[4]arene-based chiral diphosphite
ligands [(S,S)-3].
Fig. 3. Reaction profiles for the asymmetric hydrogenation of methyl-(Z)-2-
(acetamido)acrylate (1a) catalyzed by in situ generated catalysts comprised of
[Rh(COD)2BF4] and calix[4]arene-based chiral diphosphite ligands [(S,S)-3a–d]. Con-
ditions: [Rh(COD)2BF4] = 1.0 mM; [(S,S)-3a–d] = 1.5 mM; [1a] = 0.3 M; P(H2) = 5 atm;
T = 30 ◦C; CH2Cl2 solvent.
3.3. Catalytic performance
The synthesized calix[4]arene-1,3-diphosphites (3) were trialed
as chiral ligands in the Rh-catalyzed asymmetric hydrogenation of
1a and 1b (conditions: [Rh(COD)2BF4] = 1.0 mM; [(S,S)-3] = 1.5 mM;
[1a] = 0.3 M or [1b] = 0.1 M; P(H2) = 5 atm; T = 30 ◦C; VT = 3 mL, sol-
vent = CH2Cl2) [31]. The active catalyst was generated in situ from
Rh(COD)2BF4 and corresponding (S,S)-3 as obtained without fur-
ther separation of conformational isomers (where applicable),
Scheme 2. Both the catalyst activity and extent of chiral induction
were influenced by the substituents on the calixarene backbone (R1
and R2). Furthermore, the catalytic performance showed some sub-
strate dependence with overall better results obtained for the less
sterically hindered 1a. The (S,S)-catalyst generated the (R)-product
as expected from corresponding BINOL-based monophosphite [5]
and related bidentate phosphite [6,11,32] Rh-catalyzed hydrogena-
tion systems.
Better activity and selectivity was obtained using non-
conformationally flexible calixarenes which ensures a “locked”
cone conformation, Table 1. Thus, hydrogenation of 1a catalyzed by
Rh/3a–d yielded (R)-2a quantitatively in up to 98% (5–16 h) enan-
tiomeric excess (ee), while flexible 3f showed mediocre catalytic
activity [33]. Even in the presence of 3 equiv of 3f, only 46% (16 h)
and 12% (23 h) conversions were obtained for hydrogenation of
1a and 1b, respectively. The reduced activity may reflect the poor
chelating ability for 3f (see Section 3.2).
The O-alkyl substituent R2 similarly exerts an influence on cat-
alytic performance. Accordingly, hydrogenation of 1a proceeded
with quantitative yields (5–16 h) in 85, 98, 93, and 95% ee for
3a–d, respectively. The effects were more obvious for more ster-
ically demanding 1b. While the O-CH2CH2CH3 (3b) substituted
diphosphite calixarene yielded (R)-2b in 96% ee, O-(CH2)3CH3 (3c)
and O-CH2C6H5 (3d) gave (R)-2b in considerably lower ee, 64
and 76%, respectively. The steric effects are not straightforward,
however, with the less sterically hindered O-CH3 (3a) similarly
yielding (R)-2b in low ee (72%). Catalyst activity was also influ-
enced by the R2 substituent. Hydrogenation of 1b by Rh/3c only
gave 68% conversion after 21 h (entry 6, Table 1). Fig. 3 contrasts
reaction profiles for hydrogenation of 1a catalyzed by Rh/3a–d sys-
tems (conditions: [Rh(COD)2BF4] = 1.0 mM; [(S,S)-3a–d] = 1.5 mM;
[1a] = 0.3 M; P(H2) = 5 atm; T = 30 ◦C; VT = 6 mL, solvent = CH2Cl2).
The hydrogenation rates for 3a, 3c and 3d are considerably lower
than for 3b under these conditions, while the latter exhibited a
turn-over-frequency (TOF) [34] of ca. 1300 h−1 (5 atm). Thus, opti-
mum catalytic performance is obtained when the R2 group is
–CH2CH2CH3. Such variation on reactivity and selectivity have been
previously observed for related hydroformylation systems [9j,32].
Although the principle function of the upper rim para-
substituent R1 is to minimize conformational freedom, an influence
on enantioselectivity was also observed. Thus, Rh/3g catalyzed
hydrogenation yielded (R)-2a and -2b in lower 74% (cf. 95% for
3d) and 61% (cf. 76% for 3d) ee, respectively. Here, the added flex-
ibility of the P-ligand resulting from para-benzyl substitution may
account for the difference. However, electronic effects cannot be
ruled out. Hydrogenation of 1b with related bulky monophosphite
ligands have been shown to yield product with lower ee values [5c].
Modification of the BINOL-backbone resulted in considerably
lower activity and loss of chiral induction. Thus, AH of 1a with the
Rh/3e system gave (R)-2a in only 16% ee, while hydrogenation of
1b resulted in a reversal of the product chirality yielding (S)-2b
in only 23% ee. Moreover, the system required 3 equiv. of 3e and
long reaction times for high conversions reflecting the lower Rh-
chelating ability of this ligand (see Section 3.2).
Table 1
Asymmetric hydrogenation of methyl-(Z)-2-(acetamido)acrylate (1a) and methyl-
(Z)-2-(acetamido)cinnamate (1b) catalyzed by in situ generated catalysts comprised
of [Rh(COD)2BF4] and chiral calix[4]arene-based bidentate phosphite ligands (3)a.
Entry
Ligand
Substrate
Time (h)
Conv.b (%)
eec (%)
(config)d
1
2f
3
4
5
(S,S)-3ae
(S,S)-3ae
(S,S)-3be
(S,S)-3be
(S,S)-3c
(S,S)-3c
(S,S)-3d
(S,S)-3d
(S,S)-3ee
(S,S)-3ee
(S,S)-3fe
(S,S)-3fe
(S,S)-3g
(S,S)-3g
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
16
14
11
10
10
21
16
15
48
48
16
23
15
17
100
100
100
100
100
68
100
100
100
100
46
85 (R)
72 (R)
98 (R)
96 (R)
93 (R)
64 (R)
95 (R)
76 (R)
16 (R)
23 (S)
91 (R)
31 (R)
74 (R)
61 (R)
6
7
8
9f
10f
11f
12f
13
14
Typical reaction profiles for the optimum O-propyl cal-
12
100
100
ixarene Rh/3b system are shown in Fig.
4
(conditions:
[Rh(COD)2BF4] = 1.0 mM; [(S,S)-3b] = 1.5 mM; [1a] = 0.3 M or
[1b] = 0.1 M; P(H2) = 5 atm; T = 30 ◦C; VT = 6 mL, solvent = CH2Cl2).
The hydrogenation proceeded smoothly following a short incuba-
tion period without formation of any side products yielding (R)-2a
in 98% ee with a maximum TOF of 1300 h−1, and (R)-2b in 96% ee
with a TOF of 250 h−1. Product (R)-2 was generated in near constant
enantioselectivity throughout the hydrogenation for both systems.
a
Conditions: [Rh(COD)2BF4] = 1.0 mM; [3] = 1.5 mM; [1a] = 0.3 M (S/C = 300) or
[1b] = 0.1 M (S/C = 100); P(H2) = 5 atm; T = 30 ◦C; VT = 3 mL, CH2Cl2 solvent.
b
Isolated yield, conversion determined by 1H NMR.
Enantiomeric excess (ee) determined by chiral GC or HPLC.
Absolute configuration (config) determined from [␣]D measurement.
Mixture of conformational isomers.
c
d
e
f
3 equiv. of (S,S)-3 used.

S. Liu, C.A. Sandoval / Journal of Molecular Catalysis A: Chemical 325 (2010) 65–72
71
Table 2
Asymmetric hydrogenation of methyl-(Z)-2-(acetamido)acrylate (1a) and methyl-(Z)-2-(acetamido)cinnamate (1b) with in situ generated catalysts comprised of
[Rh(COD)2BF4] and chiral calix[4]arene-based bidentate phosphite ligands (3d or 3b)a.
Entry
Ligand
Substrate
S/C
300
Pressure (atm)
Temperature (◦C)
Time (h)
Conv.b (%)
eec (%) (config)d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
(S,S)-3d
(S,S)-3d
(S,S)-3d
(S,S)-3d
(S,S)-3d
(S,S)-3d
(S,S)-3d
(S,S)-3d
(S,S)-3b
(S,S)-3b
(S,S)-3b
(S,S)-3b
(S,S)-3b
(S,S)-3b
(S,S)-3b
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
5
5
5
5
5
2
8
16
5
5
20
30
50
30
50
30
30
30
20
30
50
50
30
30
30
2
2
2
12
12
13
5
4
2
2
2
25
40
76
97 (R)
96 (R)
96 (R)
95 (R)
94 (R)
97 (R)
95 (R)
93 (R)
94 (R)
96 (R)
97 (R)
92 (R)
98 (R)
93 (R)
92 (R)
300
300
1000
1000
300
300
300
100
100
100
1000
100
100
100
41
100
100
100
100
100
100
100
86
5
5
2
8
18
11
1.5
1
100
100
100
16
a
Conditions: [Rh(COD)2BF4] = 1.0 mM; [3d] = 1.5 mM; [3b] = 1.5 mM (mixture of conformational isomers); [1a] = 0.3 or 1.0 M; [1b] = 0.1 or 1.0 M; VT = 3 mL, CH2Cl2 solvent.
Isolated yield, conversion determined by 1HNMR.
Enantiomeric excess (ee) determined by chiral GC or HPLC.
b
c
d
Absolute configuration (config) determined from [␣]D measurement.
Such results are comparable with other phosphite-based ligands
[5,6,12a,32], but cannot compete with the best bisphosphine
ligands available in terms of overall efficiency [1,26,35].
going from 20 to 50 ◦C. Such findings are consistent with Halpern
kinetics involving concurrent and competitive reaction pathways
for the two possible diastereomeric intermediates [30a,36]. The
enhanced catalyst activity at higher temperature (50 ◦C) allowed
for 100 and 86% conversions for 1a (12 h) and 1b (18 h), respec-
tively, at a substrate-to-catalyst (S/C) molar ratio of 1000 (0.1 mol%
catalyst loading).
The catalysis proceeded best using CH2Cl2 (or CH2ClCH2Cl) as
solvent. Thus, although hydrogenation was quantitative in CH2Cl2
(98% ee), only 8–30% conversion (69–85% ee) was obtained in
protic solvents (MeOH, i-PrOH, t-BuOH), while 13–48% (57–88%
ee) was managed in other non-protic solvents (THF, Et2O, EtOAc,
toluene) (conditions: [Rh(COD)2BF4] = 1.0 mM; [(S,S)-3b] = 1.5 mM;
[1b] = 0.1 M; P(H2) = 5 atm; T = 30 ◦C; V (solvent) = 3 mL). Table 2
summarizes the influence of reaction parameters on the overall
catalysis during hydrogenation of 1a and 1b with in situ formed
Rh/3d and Rh/3b, respectively. Significantly, the enantioselectiv-
ity showed a small dependence on hydrogen pressure with better
ee values obtained at lower pressures. Thus, (R)-2a was obtained
in 97% ee at 2 atm and 93% ee at 16 atm under otherwise identi-
cal conditions ([Rh(COD)2BF4] = 1.0 mM; [(S,S)-3b or 3d] = 1.5 mM;
[1a] = 0.3 M or [1b] = 0.1 M; T = 30 ◦C; VT = 3 mL, solvent = CH2Cl2),
while the ee% dropped from 98 to 92% over the same range for
(R)-2b. A relatively small drop in enantioselectivity was observed
for hydrogenation of 1a with increasing temperature, 97% (20 ◦C)
and 96% (50 ◦C), while the ee% increased for 1b from 94 to 97% in
4. Conclusions
The readily modified calix[4]arene framework allowed for facile
generation of a number of chiral diphosphite functionalized lig-
ands capable of forming in situ Rh-complexes which catalyzed the
asymmetric hydrogenation of methyl acetamidoacrylate (1a) and
the corresponding cinnamate (1b). The upper rim (R1) and 1,3-O-
alkylation (R2) substituents strongly influenced the catalyst activity
and chiral induction with optimum results obtained when R1 was
–C(CH3)3 and R2 was –CH2CH2CH3 (3b). Under optimized condi-
tions, the 3b/Rh system yielded (R)-2a in up to 98% ee with a TOF
of 1300 h−1 (5 atm), and (R)-2b in 96% ee with a TOF of 250 h−1
(5 atm).
Acknowledgments
This work was supported by the Chinese Academy of Sciences
(No. O7210122R0) and the National Natural Science Foundation
(No. 20620140429).
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Fig. 4. Reaction profiles for the asymmetric hydrogenation of methyl-(Z)-2-
(acetamido)acrylate (1a) and methyl-(Z)-2-(acetamido)cinnamate (1b) catalyzed
by in situ generated catalyst comprised of [Rh(COD)2BF4] and (S,S)-3b. Conditions:
[Rh(COD)2BF4] = 1.0 mM; [(S,S)-3b] = 1.5 mM; [1a] = 0.3 M (S/C = 300); [1b] = 0.1 M
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72
S. Liu, C.A. Sandoval / Journal of Molecular Catalysis A: Chemical 325 (2010) 65–72
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´
˚
a Bruker SMART APEX-CCD diffractometer (MoK␣ radiation, ꢀ = 0.71073 A).
´
´
´
˚
˚
˚
Mr = 1389.61, hexagonal, P61, a = 14.561(6) A, b = 14.561(6) A, c = 63.93(4) A,
Z = 6, ꢁcalcd = 1.179 mg m−3, ꢂ = 0.112 mm−1, F(0 0 0) = 4440, T = 293(2) K. Refine-
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919 variables and 8135 reflections with I > 2ꢃ(I); R1 = 0.0602, wR2 = 0.1218,
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´
˚
Sw = 0.908, ꢄꢁ < 0.56 e A−1, Flack parameter = −0.250.
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yielded 2b with the same ee.
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