Impact on hydrogenation catalytic cycle of the R groups Cyclic feature in "r-SMS-Phos"

Article abstract of DOI:10.1021/ol101029s

A series of R-SMS-Phos ligands was evaluated in the Rh(I)-catalyzed hydrogenation of a set of olefins showing a marked influence of the cyclic nature and structure of the R groups. Overall, cPen- and Cy-SMS-Phos performed efficiently, while Ph- and Bn-SMS-Phos exhibited slower kinetics and furnished lower ees also compared with C₆F₅CH₂-SMS-Phos. The Rh(I)-(Cy-SMS-Phos) catalyst was screened under mild conditions displaying excellent enantioselectivities and high TOFs. Cases of catalysis under catalyst or substrate control were identified.

Full text of DOI:10.1021/ol101029s

ORGANIC
LETTERS
2010
Vol. 12, No. 13
3022-3025
Impact on Hydrogenation Catalytic
Cycle of the R Groups’ Cyclic Feature in
“R-SMS-Phos”
Borut Zupancˇicˇ,† Barbara Mohar,† and Michel Stephan*,†,‡
Laboratory of Organic and Medicinal Chemistry, National Institute of Chemistry,
HajdrihoVa 19, SI-1001 Ljubljana, SloVenia, and PhosPhoenix SARL, 115,
rue de l’Abbe´ Groult, F-75015 Paris, France
mstephan@phosphoenix.com; michel.stephan@ki.si
Received May 5, 2010
ABSTRACT
A series of R-SMS-Phos ligands was evaluated in the Rh(I)-catalyzed hydrogenation of a set of olefins showing a marked influence of the
cyclic nature and structure of the R groups. Overall, cPen- and Cy-SMS-Phos performed efficiently, while Ph- and Bn-SMS-Phos exhibited
slower kinetics and furnished lower ee’s also compared with C6F5CH2-SMS-Phos. The Rh(I)-(Cy-SMS-Phos) catalyst was screened under mild
conditions displaying excellent enantioselectivities and high TOFs. Cases of catalysis under catalyst or substrate control were identified.
Undoubtedly, promoted by chiral Rh, Ru, or Ir complexes of
phosphorus-based ligands, asymmetric hydrogenation of pros-
tereogenic olefins offers a viable cost-effective alternative for
the production of enantiopure bioactive ingredients or their
components.1 Nevertheless, in the race to ally high enantiose-
lectivity with high catalytic activity, catalysis proved to be
critically sensitive to the ligand structure. In particular, P-
stereogenic diphosphines have indelibly marked and advanced
this technology on both the applied and fundamental levels.1,2
In our continuing research on Rh(I)-(P-stereogenic phos-
phine)-catalyzed hydrogenation of olefins,3 we present herein
our comparative study and application of a new 1,2-bis-
[(o-RO-phenyl)(phenyl)phosphino]ethane (R-SMS-Phos) se-
ries wherein R ) cPen, Cy, Ph, Bn, and C6F5CH2 with the
various R groups sharing a common cyclic feature.
† National Institute of Chemistry.
‡ PhosPhoenix SARL.
(1) (a) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vols. 1-3. (b) Asymmetric
Catalysis on Industrial Scale; Blaser, H. U., Schmidt, E., Eds.; Wiley-VCH:
Weinheim, 2004. (c) Handbook of Homogeneous Hydrogenation; de Vries,
J. G., Elsevier, C. J., Eds.; Wiley-VCH: Weinheim, 2006; Vols. 1-3.
(2) Following publications and references cited therein: (a) Knowles,
W. S. Angew. Chem., Int. Ed. 2002, 41, 1998–2007. (b) Tang, W.; Zhang,
X. Chem. ReV. 2003, 103, 3029–3069. (c) Grabulosa, A.; Granell, J.; Muller,
G. Coord. Chem. ReV. 2007, 251, 25–90. (d) Phosphorus Ligands in
Asymmetric Catalysis; Bo¨rner, A., Ed.; Wiley-VCH: Weinheim, 2008; Vols.
Readily prepared in 46-76% overall yields via the easy-
to-perform Juge´-Stephan route4 or from the crystalline
(3) (a) Stephan, M.; Mohar, B. FR2887253, 2005; WO2006136695,
2006. (b) Zupancˇicˇ, B.; Mohar, B.; Stephan, M. AdV. Synth. Catal. 2008,
ˇ
350, 2024–2032. (c) Stephan, M.; Sterk, D.; Mohar, B. AdV. Synth. Catal.
2009, 351, 2779-2786. (d) Zupancˇicˇ, B.; Mohar, B.; Stephan, M. Tetra-
hedron Lett. 2009, 50, 7382–7384. (e) Zupancˇicˇ, B.; Mohar, B.; Stephan,
M. Org. Lett. 2010, 12, 1296–1299.
1-3
.
10.1021/ol101029s  2010 American Chemical Society
Published on Web 06/02/2010

Table 1. [Rh((R,R)-R-SMS-Phos)(MeOH)2]BF4-Catalyzed Hydrogenation of S1-S7a
a The catalyst was prepared in situ from [Rh(nbd)2]BF4. Runs were carried out under 1 bar of H2 (10 bar for S7) at rt in MeOH (0.5 mmol of substrate
in 7.5 mL of MeOH) with a substrate/catalyst ratio (S/C) ) 100 (S/C ) 1000 for S1) for the time indicated (100% conversion) if not stated otherwise and
are unoptimized. Typical isolated yields were >90%. Ee’s were determined by chiral GC (prior to analysis, the carboxylic group of the hydrogenation
product of S7 was esterified with TMSCHN2). With (R,R)-R-SMS-Phos, S-configured products were obtained except with S6. b 92% conversion. c 77%
conversion. d In the presence of Et3N (1.1 equiv). e 53% conversion.
1,2-bis[(o-hydroxyphenyl)(phenyl)phosphino-P-borane]-
ethane,3a the R-SMS-Phos series was assessed under mild
conditions in the asymmetric hydrogenation of an indicative
set of olefinic substrates S1-S7 (Table 1). The Rh(I)-(R-
SMS-Phos)-catalyzed hydrogenation proved to be affected
by the cyclic nature and structure of the R groups. The cPen-
and Cy-SMS-Phos ligands emerged as being superior,
whereas Ph-SMS-Phos presented the lowest ee values
followed by Bn-SMS-Phos. Interestingly, the latter’s per-
fluorinated-ring analogue C6F5CH2-SMS-Phos behaved in
comparison to it noticeably better. Consequently, in the case
of the Bn-SMS-Phos ligand, a deleterious interference of a
Bn group with the Rh center appears to be attributable.
oselectivity attained in such catalysis for the corresponding
benchmark substrate.3
Investigating further the scope of the Rh(I)-(Cy-SMS-
Phos) catalyst in hydrogenation, this was screened under mild
conditions against a selection of a broad diversity of
challenging and new olefins S7-S24 (Table 2). Bn-
substituted olefins (S9, S19, and S24) were considered as
well. Overall, high reaction rates coupled with good to
excellent ee’s were obtained ranking among the top values
reported in the literature for the hydrogenation of the
corresponding substrates.5
Under the adopted standard reaction conditions, the Rh(I)-
(Cy-SMS-Phos) complex was effective in catalyzing the
hydrogenation of a series of ꢀ-substituted and ꢀ,ꢀ-disubsti-
tuted dehydro-(N-acetyl)alaninates S8-S12 with >99% ee
and good reaction rates. In particular, methyl (Z)-2-aceta-
mido-3-(3-pyridyl)propenoate (S8) in the form of its HBF4
salt was hydrogenated with 99.6% ee within 24 h using a
S/C 30 000. With comparable efficiency, ethyl R-acetamido-
vinylphosphonate (S13) led to 99.9% ee within a few hours
Thus, operating with a S/C 100 in MeOH at rt under 1
bar of H2, the classical test substrates methyl R-acetamido-
acrylate (S1: MAA) and cinnamate (S2: MAC) were
hydrogenated invariably with >99% ee’s within minutes,
except for Ph-SMS-Phos which afforded ee’s up to 97.1%.
The Cy-SMS-Phos performed the best in the hydrogenation
of methyl (Z)-3-acetamidobut-2-enoate (S3: (Z)-MAB) and
its (E)-isomer (S4: (E)-MAB) attaining 88.2% and 97.8%
ee, respectively. R-Acetamidostyrene (S5: AS) and dimethyl
itaconate (S6: DMI) were hydrogenated within minutes with
>99% ee using cPen- or Cy-SMS-Phos, and the performance
of C6F5CH2-SMS-Phos was quite close. Notably, the hydro-
genation of atropic acid (S7: AA) using cPen- and Cy-SMS-
Phos proceeded within 2 h leading to 96.4% and 97.1% ee,
respectively. The latter result represents the highest enanti-
(4) Juge´, S.; Stephan, M.; Laffitte, J. A.; Geneˆt, J.-P. Tetrahedron Lett.
1990, 31, 6357–6360.
(5) For indicative literature data regarding metal-catalyzed hydrogenation
of the known substrates or derivatives with representative phosphorus-based
ligands, see the Supporting Information.
(6) (a) Talley, J. J. US5321153, 1994. (b) Breipohl, G.; Holla, W.;
Jendralla, H.; Beck, G. WO55175, 2001. (c) Zeng, Q.; Liu, H.; Mi, A.;
Jiang, Y.; Li, X.; Choi, M. C. K.; Chan, A. S. C. Tetrahedron 2002, 58,
8799–8803. (d) Blaser, H.-U.; Pugin, B.; Spindler, F. J. Mol. Catal. A:
Chem. 2005, 231, 1–20.
Org. Lett., Vol. 12, No. 13, 2010
3023

Table 2. [Rh((R,R)-Cy-SMS-Phos)(MeOH)2]BF4-Catalyzed Hydrogenation of Miscellaneous Classes of Olefinsa
a The catalyst was prepared in situ from [Rh(nbd)2]BF4 and (R,R)-Cy-SMS-Phos. Runs were carried out under 1 bar of H2 (3 bar for S10, S12, S19 and
10 bar for S7, S16, S18, S20, S23) at rt in MeOH (0.5 mmol of substrate in 7.5 mL of MeOH with a S/C ) 100 or 1000; 10 mmol of substrate in 7.5 mL
of MeOH with a S/C ) 10 000; 30 mmol of substrate in 20 mL of MeOH with a S/C ) 30 000; 50 mmol of substrate in 40 mL of MeOH with a S/C )
50 000) for the time indicated (100% conversion). Typical isolated yields were >90%. Ee’s were determined by: chiral GC for S7-S14, S16-S19, S21
(prior to analysis, the carboxylic groups of hydrogenation products of S7, S11, S14, S16, S18, and S19 were esterified with TMSCHN2); chiral HPLC for
S15, S22-S24; 31P NMR in the presence of (+)-ephedrine for hydrogenation product of S20. b In the presence of HBF4·Et2O (1.1 equiv); in the absence of
HBF4 (S/C ) 100), a 40% conversion and 93.8% ee (S) were attained in 18 h. c 10 bar of H2. d In the presence of t-BuNH2 (1.1 equiv). e In the presence
of Et3N (0.05 equiv). f In the presence of Cy2NH (0.05 equiv). g In the presence of Cy2NH (1.1 equiv). h 1H NMR analysis revealed that the 1,2-diphenylpropane
(84%) was accompanied with R-methylstilbene (13% trans, 3% cis). i 1H NMR analysis revealed that the 1,2-diphenylpropane (96%) was accompanied with
R-methylstilbene (3% trans, <1% cis). j 50 bar of H2.
using a S/C 50 000. Such unusual amino acids and simple
reaction conditions are of industrial relevance.6
However, while the ethyl ester S17 was converted into the
R-configured product equivalent of Roche ester with the
highest reported hydrogenation ee (97.8% ee),5 a reverse of
stereoselectivity but still with high induction (93.2% ee) was
observed with the dicyclohexylammonium salt derivative
S16.9 Projected mechanistic studies may elucidate the binding
mode of these olefins to the Rh core and the underlying
catalysis picture.
Conversely to the typical low enantioselectivity (<10% ee)
encountered in the hydrogenation of the notorious R-meth-
ylideneglutaric acid derivatives in alcohols,10 the monoester
S18 afforded as high as 81.2% ee.
Moreover, two pairs of R-amidomethyl- (S14, S15) and
R-hydroxymethyl-acrylic acid derivatives (S16, S17) under-
went hydrogenation with particularly high ee’s. Whereas the
Ru-mediated catalysis largely dominated the hydrogenation
of R-amidomethylacrylates with limited efficiency,7 the
hydrogenation of S14 under our practical protocol afforded
>99% ee within minutes. Analysis of the hydrogenation
outcome of substrates S8-S15 indicated an identical sense
of hydrogenation in accordance with the quadrant rule8 and
taking into account the switch in the groups’ priorities.
Furthermore, while the hydrogenation (10 bar of H2, 2 h)
of atropic acid (S7: AA) proceeded equally well in the
(7) (a) Takagi, M.; Yamamoto, K. Tetrahedron 1991, 47, 8869–8882.
(b) Dellis, P.; Gueirrero, P.; Geneˆt, J.-P. FR2801886, 2001. (c) Takagi,
M.; Yamamoto, K. Tetrahedron: Asymmetry 2001, 12, 657–667. (d) Saylik,
D.; Campi, E. M.; Donohue, A. C.; Jackson, W. R.; Robinson, A. J.
Tetrahedron 2002, 58, 8799–8803. (e) Huang, H.; Liu, X.; Deng, J.; Qiu,
M.; Zheng, Z. Org. Lett. 2006, 8, 3359–3362.
(8) Valid for amino acids, the empirical quadrant rule suggests that (S)-
R-amino acids are obtained using (R,R)-DiPAMP-type ligands and vice
versa. For this, see: ref 2a. .
(9) Krawczyk, H. Synth. Commun. 1995, 25, 641–650.
3024
Org. Lett., Vol. 12, No. 13, 2010

presence of 5 mol % of Cy2NH furnishing 97.4% ee, its
higher homologue R-benzylacrylic acid (S19) necessitated
the addition of 1.1 equiv of Cy2NH to achieve up to 74.9%
ee (10 bar of H2, 3 h). Interestingly, AA’s phosphonic
analogue S20 was hydrogenated under similar conditions
within 3 h albeit with 84.8% ee. Still, the latter result is the
highest value reported for the corresponding substrate.5
In conclusion, this exploratory investigation highlighted
the prospects of the R-SMS-Phos family and demonstrated
that the hydrogenation using the [Rh(R-SMS-Phos)(MeOH)2]
catalysts is markedly affected by the cyclic nature and
structure of the R groups. The noncoordinating and inherent
bulky Cy group bestowed interesting attributes on the
[Rh(Cy-SMS-Phos)(MeOH)2] catalyst displaying excellent
ee’s and high TOFs in the hydrogenation under mild
conditions of a host of olefins. The degree and sense of
enantioselection continue to be intrinsically dependent on
the bulkiness and electronic properties of the various
coordinating groups present in the medium as well as on
the reaction conditions.
Proceeding with our screening, the simplest R-arylvinyl
acetate S21 and methyl R-benzoyloxy-vinylphosphonate
(S22) were hydrogenated once again3e reasonably fast and
with high ee’s. In the case of the latter substrate, a 99.8%
ee was maintained with full conversion within 3 h using a
S/C 10 000. Also, up to 93.0% ee was reached in the
hydrogenation of methyl R-styryl ketoxime (S23).
Finally, we explored the hydrogenation of R-benzylstyrene
(S24)11 with disappointing results. Poor ee’s in the range of
9-23% were obtained with a concurrent competing Rh-
catalyzed isomerization-hydrogenation sequence. Nonethe-
less, it seems that a different catalytic cycle is active at higher
pressures as an inversion of stereodirection occurred shifting
from 1-10 to 50 bar of H2.
Acknowledgment. This work was supported by the
Ministry of Higher Education, Science, and Technology of
the Republic of Slovenia (Grant No. J1-9806) and by the
Ministry of National Education, Research, and Technology
of France (Grant No. 00P141 to PhosPhoenix SARL). We
thank Prof. Henryk Krawczyk (Technical University of Ło´dz´,
Poland) for the gift of S16.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(10) (a) Christopfel, W. C.; Vineyard, B. D. J. Am. Chem. Soc. 1979,
101, 4406–4407. (b) Duan, Z.-C.; Hu, X.-P.; Deng, J.; Yu, S.-B.; Wang,
D.-Y.; Zheng, Z. Tetrahedron: Asymmetry 2009, 20, 588–592.
(11) For an early basic study with S24, see: Horner, L.; Siegel, H.
Phosphorus 1972, 1, 209–216.
OL101029S
Org. Lett., Vol. 12, No. 13, 2010
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