A convenient synthesis of 2,2′,6,6′-tetramethoxy-4,4′- bis(dicyclohexylphosphino)-3,3′-bipyridine (Cy-P-Phos): Application in Rh-catalyzed asymmetric hydrogenation of α-(acylamino)acrylates

Article abstract of DOI:10.1002/adsc.200404310

The first example of the synthesis of an axially chiral bis(aryldicyclohexylphosphine) dioxide via catalytic hydrogenation of the optically resolved parent bis(aryldipnenylphosphine) dioxide was reported. The procedure for the synthesis of Cy-P-Phos (4d)

Full text of DOI:10.1002/adsc.200404310

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A Convenient Synthesis of 2,2’,6,6’-Tetramethoxy-
4,4’-bis(dicyclohexylphosphino)-3,3’-bipyridine (Cy-P-Phos):
Application in Rh-Catalyzed Asymmetric Hydrogenation of
a-(Acylamino)acrylates
Jing Wu, Terry T.-L. Au-Yeung, Wai-Him Kwok, Jian-Xin Ji, Zhongyuan Zhou,
Chi-Hung Yeung,* Albert S. C. Chan*
Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis and
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
Fax: (þ852)-2364-9932, e-mail: bcachan@polyu.edu.hk
Received: October 11, 2004; Accepted: January 3, 2005
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The first example of the synthesis of an ax-
ially chiral bis(aryldicyclohexylphosphine) dioxide
via catalytic hydrogenation of the optically resolved
parent bis(aryldiphenylphosphine) dioxide was re-
ported. The procedure for the synthesis of Cy-P-
Phos (4d) has thus successfully avoided the need
for an otherwise lengthy synthetic route owing to
the p-excessive nature of one of the aryl groups in
the latter. The use of Cy-P-Phos in the Rh(I)-cata-
lyzed asymmetric hydrogenation of the derivatives
of methyl (Z)-2-acetamidocinnamate gave signifi-
cantly higher rates of reaction as compared to the
use of the previously reported optimal ligand Xyl-
P-Phos (4c) whilst the level of enantioselectivity
was essentially maintained.
control, especially in catalytic asymmetric reactions
where the oxidative addition is one of the rate-determin-
ing steps. For instance (Scheme 1), Josiphos 1 is industri-
ally employed for the hydrogenation of an imine leading
to the synthesis of metolachlor,[1] MAP 2 is efficient in
asymmetric Suzuki coupling,[2] vinylation[3] and aryla-
tion[4] of ketone enolates, and trans-1,2-bis(dicyclohex-
ylphosphino)cyclohexane 3 is utilized in asymmetric hy-
droboration of styrene derivatives.[5] The dicyclohexyl-
phosphine version in theses cases shows remarkably bet-
ter performance, in terms of both enantioselectivity and
reactivity, as compared to its diphenylphosphine ana-
logues.
We have recently synthesized a class of atropisomeric
dipyridylphosphine ligands, P-Phos (4a) and its deriva-
tives 4b – 4c (Scheme 2)[6] and have established their ef-
fectiveness in many catalytic asymmetric hydrogenation
reactions[6,7] including the Ru- and Rh-catalyzed asym-
metric hydrogenation of methyl esters of a variety of
(Z)-2-acetamido-3-arylacrylic acids and various b-al-
kyl-substituted b-(acylamino)acrylates to provide deriv-
Keywords: a-(acylamino)acrylates; asymmetric hy-
drogenation; dipyridylphosphine; homogeneous cat-
alysis; rhodium
In a transition metal-catalyzed process, the electronic
property of the ligand usually plays a crucial role in de-
termining the reactivity of the catalyst. When phos-
phines are used as ligands, their electronic properties
can be tuned by attaching various P-substituents (alkyl
groups for electron-rich phosphines and aryl groups
for comparatively electron-poor phosphines in general).
The situation, however, can be confounded when the
stereochemical outcome needs to be controlled, par-
ticularly so when the non-P-chirogenic dialkylphosphi-
no group, often known for its inefficient stereodifferen-
tiability, is required to promote appreciable reactivity.
Nevertheless, the fully saturated dicyclohexylphosphine
Scheme 1. Some chiral ligands containing dicyclohexylphos-
group sometimes displays unique stereo- and electronic phine group.
Adv. Synth. Catal. 2005, 347, 507–511
DOI: 10.1002/adsc.200404310
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Jing Wu et al.
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It therefore appeared inevitable at first sight to repeat
the above pathway, which encompasses a tedious resolu-
tion as in the synthesis of chiral Cy-BICHEP[9] or Cy-
BINAP[10] for the synthesis of 4d. However, capitalizing
on the fact that p-excessive aromatic rings are very dif-
ficult to hydrogenate, we conjectured that it might be
possible to reduce the phenyl groups in 8a via metal-cat-
alyzed hydrogenation whilst leaving the heterocyclic
ring intact and giving a bis(aryldialkylphosphine) diox-
ide. Although the idea of obtaining bis(dicyclohexyl-
phopshine) dioxides via hydrogenation of the parent
bis(diphenylphosphine) dioxides has been reported, its
application has been limited only to the synthesis of bi-
s(alkyldicyclohexylphosphine) dioxides.[11]
In the initial attempt, it was found that the Pd/C sys-
tem failed to catalyze the hydrogenation of (ꢀ)-8a to
(ꢀ)-9 (Scheme 4) in the mixture of ethanol and acetic
acid under 500 psi hydrogen pressure at 508C after 36
hours. However, when the catalyst was switched to
PtO2 and the reaction was performed in acetic acid, a
mixture of the desired (ꢀ)-9 and partially hydrogenated
(ꢀ)-10 (molar ratio¼5:1 according to 1H and 31P NMR
analyses) resulted after 72 hours at room temperature
Scheme 2. Chiral dipyridylphosphine ligands 4.
atives of a- or b-amino acids.[8] In view of the potential (Scheme 4). The ratio of (ꢀ)-9 and (ꢀ)-10 was further
usefulness of the dicyclohexylphosphino group as de- improved to 10:1 when the reaction temperature was in-
scribed above, we were interested in probing its efficacy creased to 508C within the same reaction time frame. Fi-
in connection to the six-membered biheteroaryl P-Phos nally, pure (ꢀ)-9 was obtained as the exclusive product
skeleton. This had led us to develop a convenient syn- by simply prolonging the reaction time to 120 hour at
thetic route to Cy-P-Phos [4d, 2,2’,6,6’-tetramethoxy- 508C. Thus, under the same conditions, optically pure
4,4’-bis(dicyclohexylphosphino)-3,3’-bipyridine].
9 was obtained from the hydrogenation of the corre-
The synthesis of each of the P-Phos members 4a–4c sponding enantiomer of 8a. Single crystals of (S)-9
entails the introduction of the phosphinoyl group onto were obtained by recrystallization in methanol, and
2,6-dimethoxypyridine before a Cu-mediated Ullmann the structure of (S)-9 was unambiguously determined
coupling process to afford the racemic C2-symmetric di- by single crystal X-ray diffraction analysis.[12] Reduction
phosphine dioxide 8. The chiral diphosphine is obtained of enantiomerically pure 9 with trichlorosilane in the
by optical resolution with enantiopure dibenzoyltartaric presence of triethylamine in toluene afforded the target-
acid (DBTA) followed by reduction with trichlorosilane ed enantiomer of atropisomeric ligand 4d in 53% yield.
1
in overall 6 steps as outlined in Scheme 3.[6]
The compound was fully characterized by H, 13C, and
Scheme 3. The synthetic route towards 4a–4c.
508
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2,2’,6,6’-Tetramethoxy-4,4’-bis(dicyclohexylphosphino)-3,3’-bipyridine
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Scheme 4. The synthetic route towards 4d.
31P NMR spectroscopy, mass spectrometry and elemen- Table 1. The effects of solvent, hydrogen pressure and reac-
tion temperature on the hydrogenation of methyl (Z)-2-acet-
tal analysis.
amidocinnamate (11) catalyzed by [(S)-4d-Rh(COD)]BF4.[a]
Next, the rhodium complex [4d-Rh(COD)]BF4 was
prepared in situ by mixing Rh(COD)2BF4 with 1.05
equivalents of 4d in dichloromethane under nitrogen.
The 31P NMR spectrum of the resulting complex in
CDCl3 exhibited two sets of doublet-of-doublets signals
respectively centered at d¼12.7 (JRh,P ¼145 Hz, JP, P
¼
23.7 Hz) and 24.3 (JRh,P ¼124.0 Hz, JP, P ¼23.7 Hz). This
is somehow intriguing as the intuitively C2-symmetric
complex turned out to be non-symmetric in solution
and is in sharp contrast to the analogous Rh(I) com-
plexes formed from the other members of the P-Phos
family.[8] This observation was consistent with a reported
X-ray crystal structure of [Rh(S-Cy-BINAP)(COD)]-
ClO4, which differed distinctly from similar Rh com-
plexes derived from C2-symmetric bisphosphines bear-
ing four P-phenyl rings, in that it did not approximate
to C2-symmetry.[10] The four cyclohexyl groups appear
to be disposed in an edge-face-face-face arrangement
rather than in an edge-face-edge-face orientation and
the seven-membered chelate ring was remarkably dis-
torted from a d-skew conformation. The non-equiva-
lence of the two phosphorus atoms in [Rh(S-Cy-BI-
NAP)(COD)]ClO4 was also reflected in the distinctly
variable Rh-P distances [2.331(2) and 2.422(2) ꢁ for
P(1) and P(2), respectively] and in the 31P NMR spec-
trum [d¼12.1 (dd, JRh,P ¼145.7 Hz, JP, P ¼19.9 Hz) and
31.1 (dd, JRh,P ¼125.2 Hz, JP, P ¼19.9 Hz)].[10]
Entry
Solvent
H2 [atm]
T [ 8C]
ee [%][b]
1
Methanol
Methanol
THF
1
1
1
1
1
rt
0
90 (90)[c]
2[d]
3
93 (94)[c]
rt
rt
rt
rt
rt
rt
0
89
78
94
95
87
86
97
4
5
6
7
CH2Cl2
Toluene
Acetone
Acetone
Acetone
Acetone
1
15
35
1
8
9[d]
[a]
Reaction conditions: 2 hours; 4.4 mg substrate; substrate
concentration¼0.09 M; substrate/catalyst¼100 (M/M),
100% conversion was observed in all cases.
The conversions and ee values were determined by chiral
GC with a 25 mꢁ0.25 mm Chrompack Chirasil-L-Val col-
umn.[13] The R configuration was obtained for all products.
The absolute configuration was determined by comparing
the retention time with that reported in the literature
(Ref.[13]).
The value in parenthesis represents the enantioselectivity
achieved by [4c-Rh(COD)]BF4 under otherwise identical
conditions.[8a]
Reaction time¼8 h.
[b]
[c]
[d]
For the evaluation of the effectiveness of 4d, we select-
ed one of the most popular test reactions – the rhodium-
catalyzed enantioselective hydrogenation of methyl
(Z)-2-acetamidocinnamates. High enantioselectivity methanol was the preferred solvent for Rh-catalyzed hy-
was achieved (up to 98% ee) by the employment of drogenation of methyl esters of a variety of (Z)-2-acet-
Cy-BICHEP as chiral ligand in the rhodium-catalyzed amido-3-arylacrylic acids when using 4a–4c as chiral li-
enantioselective hydrogenation of ethyl (Z)-2-acetami- gands.[8a] Under the preferred conditions in the use of
docinnamates.[9] Our previous work indicated that 4a–4c, 4d possessed similar enantioselectivity (90%
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Jing Wu et al.
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Table 2. Asymmetric hydrogenation of the derivatives of methyl (Z)-2-acetamidocinnamate catalyzed by [(S)-4d-Rh(COD)]BF4.[a]
ee [%][b]
¼
Entry
Substrate, R
Time [h]
T [ 8C]
1
2
3
4
5
6
7
8
9
H
2-Cl
2-Cl
3-Cl
3-Cl-
4-Cl
4-Cl
4-CH3
4-CH3O
8
2
8
2
8
2
8
8
8
0
rt
0
rt
0
rt
0
97
87
90
91
92
89
91
93
95
0
0
[a]
Reaction conditions: 4 mg substrate; 1 atm hydrogen pressure; substrate concentration¼0.075 M in acetone; substrate/cat-
alyst¼100 (M/M), 100% conversion was observed in all cases.
[b]
The conversions and ee values were determined by NMR and chiral GC with a 25 mꢁ0.25 mm Chrompack Chirasil-L-Val
column.[13] The R configuration was obtained for all products. The absolute configuration was determined by comparing the
retention time with that reported in the literature (Ref.[13]).
ee, Table 1, entry 1) with the optimal ligand 4c for the merically pure parent bis(aryldiphenylphosphine) diox-
asymmetric hydrogenation of methyl (Z)-2-acetamido- ide 8a. Because of the p-excessive nature of one of the
cinnamate (11). When the experiment was performed aryl groups in the latter, this procedure has successfully
at 08C, the rate of hydrogenation effected by [4d- avoided the need for an otherwise lengthy synthetic
Rh(COD)]BF4 (8 h, entry 2) was accelerated over two- route. The use of 4d in the Rh(I)-catalyzed asymmetric
fold when compared with the analogous Rh(I) com- hydrogenation of the derivatives of methyl (Z)-2-acet-
plexes derived from 4c under otherwise identical condi- amidocinnamate showed substantially higher reaction
tions (18 h)[8a] whilst the level of enantioselectivity was rates as compared to that obtained using previously re-
essentially maintained, indicative of the beneficial effect ported optimal ligand 4c whilst the level of enantioselec-
of the electron-rich dicyclohexylphosphino moiety. Fur- tivity was essentially maintained. Further work is cur-
thermore, by carrying out the reaction in a variety of rently in progress aiming at broadening the application
common organic solvents, we found that acetone was of this ligand in other asymmetric reactions.
the most preferable solvent for the enantioselective hy-
drogenation of 11 catalyzed by [4d-Rh(COD)]BF4 (Ta-
ble 1, entry 6 vs. entries 1 and 3–5). As with many other
ligands investigated in this reaction, the use of a low hy-
drogen pressure was conducive to selectivity (Table 1,
entries 7 and 8 vs. entry 6). Also, the reaction was best
Experimental Section
performed at a lower temperature for achieving excel-
lent selectivity (entry 9 vs. entry 5).
Preparation of the Stock Solution of [(S)-4d-
Rh(COD)]BF4
Further studies of the hydrogenation of other prochiral
acetamidoacrylic esters confirmed that the enantioselec-
tivity of [4d-Rh(COD)]BF4 was quite consistent. A vari-
ety of derivatives of methyl (Z)-2-acetamidocinnamate
were hydrogenated with this catalyst and in most cases
the desired products were found to have ee values of ꢂ
90%. More detailed data are summarized in Table 2. It
was found that the presence of electron-donating groups
on the phenyl group of methyl (Z)-2-acetamidocinna-
mate led to slightly more favorable ees than electron-
withdrawing groups (entries 8 and 9 vs. entries 3, 5 and 7).
In summary, we have reported the first example of the
synthesis of an axially chiral bis(aryldicyclohexylphos-
(S)-Cy-P-Phos [(S)-4d, 7.0 mg, 10.5 mmol] was dissolved in
CH2Cl2 (0.5 mL) under nitrogen. A solution of [Rh(COD)2]BF4
(4.1 mg, 10.0 mmol) in CH2Cl2 (0.5 mL) was added dropwise
totheabovesolutionwithstirring. Thereaction mixture was stir-
red overnight to give a solution of [(S)-4d-Rh(COD)]BF4
(0.01 mol·Lꢃ1). 31P NMR (CDCl3, 202 MHz): d¼12.7 (JRh,P
145 Hz, JP, P ¼23.7 Hz), 24.3 (JRh,P ¼124.0 Hz, JP, P ¼23.7 Hz.
¼
Procedures for the Synthesis of (S)-4d
phine) 4d via the catalytic hydrogenation of the enantio- See Supporting Information.
510
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2,2’,6,6’-Tetramethoxy-4,4’-bis(dicyclohexylphosphino)-3,3’-bipyridine
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[6] P-Phos¼ 2,2’,6,6’-tetramethoxy-4,4’-bis(diphenylphos-
phino)-3,3’-bipyridine; Tol-P-Phos2,2’,6,6’-tetrame-
Typical Procedure for the Asymmetric Hydrogenation
of Methyl (Z)-2-Acetamidocinnamate
thoxy-4,4’-bis[di(p-tolyl)phosphino]-3,3’-bipyridine; Xyl-
P-Phos¼2,2’,6,6’-tetramethoxy-4,4’-bis[di(3,5-dimethyl-
phenyl)phosphino]-3,3’-bipyridine; a) C.-C. Pai, C.-W.
Lin, C.-C. Lin, C.-C. Chen, A. S. C. Chan, W. T. Wong,
J. Am. Chem. Soc. 2000, 122, 11513; b) J. Wu, H. Chen,
Z.-Y. Zhou, C.-H. Yeung, A. S. C. Chan, Synlett 2001,
1050; c) J. Wu, H. Chen, W.-H. Kwok, K.-H. Lam,
Z.-Y. Zhou, C.-H. Yeung, A. S. C. Chan, Tetrahedron
Lett. 2002, 43, 1539.
A solution of 0.01 mol·Lꢃ1 [(S)-4d-Rh(COD)]BF4 in CH2Cl2
(20 mL, 2ꢁ10ꢃ4 mmol), methyl (Z)-2-acetamidocinnamate
(4.37 g, 0.02 mmol) and acetone (200 mL) were charged to a
25-mL round-bottom flask equipped with a magnetic stirring
bar under a nitrogen atmosphere. A stream of H2 was bubbled
through the solution while it was magnetically stirred at ambi-
ent temperature for 2 h. The conversion and the enantiomeric
excess of the product (R)-2-acetamido-3-phenylpropanoate
[(R)-12] were determined by NMR and chiral GC analysis to
be>99.9% and 95%, respectively (column, Chrompack Chir-
asil-L-Val, 25 mꢁ0.25 mm, carrier gas, N2).[13]
[7] a) J. Wu., H. Chen, W. H. Kwok, R. W. Guo, Z. Y. Zhou,
C. H. Yeung, A. S. C. Chan, J. Org. Chem. 2002, 67, 7908;
b) J. Wu, J.-X. Ji, R. Guo, C.-H. Yeung, A. S. C. Chan,
Chem. Eur. J. 2003, 9, 2963.
[8] a) J. Wu, C. Pai, W. H. Kwok, R. W. Guo, T. T. L. Au-
Yeung, C. H. Yeung, A. S. C. Chan, Tetrahedron: Asym-
metry 2003, 14, 987–992; b) J. Wu, X. Chen, R. Guo,
C.-H. Yeung, A. S. C. Chan, J. Org. Chem. 2003, 68, 2490.
[9] A. Miyashita, H. Karino, J.-i. Shimamura, T. Chiba, K.
Nagano, H. Nohira, H. Takaya, Chem. Lett. 1989, 1849.
[10] X. Zhang, K. Mashima, K. Koyano, N. Sayo, H. Kumo-
bayashi, S. Akutagawa, H. Takaya, J. Chem. Soc. Perkin
Trans. 1 1994, 2309.
Acknowledgements
We thank the University Grants Committee Area of Excellence
Scheme in Hong Kong (AoE P/10–01) and The Hong Kong
Polytechnic University ASD Fund for financial support of this
study.
[11] H. Krause, C. Dçbler, Catal. Lett. 1991, 8, 23.
[12] Crystallographic data (excluding structure factors) for
the structures reported in this paper have been deposited
with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC-250704 Cop-
ies of the data can be obtained, free of charge, on appli-
cation to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [fax: þ44(0)-1223-336033 or e-mail: deposit@ccdc.-
cam.ac.uk].
References and Notes
[1] H.-U. Blaser, Adv. Synth. Catal. 2002, 344, 17 and refer-
ences cited therein.
[2] J. Yin, S. L. Buchwald, J. Am. Chem. Soc. 2000, 122,
12051.
[3] A. Chieffi, K. Kamikawa, J. ꢁhman, J. M. Fox, S. L.
Buchwald, Org. Lett. 2001, 3, 1897.
[4] T. Hamada,; A. Chieffi, J. ꢁhman, S. L. Buchwald, J. Am.
Chem. Soc. 2002, 124, 1261.
[13] A. S. C. Chan, W. Hu, C.-C. Pai, C.-P. Lau, Y. Jiang, A.
Mi, M. Yan, J. Sun, R. Lou, J. Deng, J. Am. Chem. Soc.
1997, 119, 9570.
[5] S. Demay, F. Volant, P. Knochel, Angew. Chem. Int. Ed.
2001, 40, 1235.
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