Fine-tuning monophosphine ligands for enhanced enantioselectivity. Influence of chiral hemilabile pendant groups

Article abstract of DOI:10.1021/ol0495063

C₂-Symmetric P-(2-X-aryl)-2,5-dialkylphospholanes (X = dioxolan-2-yl or dioxan-2-yl), designed on the basis of a working model for asymmetric induction, are effective ligands for the Ni(II)-catalyzed asymmetric hydrovinylation of styrenes. Excellent yields (>99%), selectivities for the desired 3-arylbutenes (>99%), high S/C ratios (>1200), and ee's (up to 91%) have been realized for a number of prototypical vinylarenes. In the dioxolane series, the selectivity depends on the configuration of the C ₄ and C₅ carbons.

Full text of DOI:10.1021/ol0495063

ORGANIC
LETTERS
2004
Vol. 6, No. 9
1515-1517
Fine-Tuning Monophosphine Ligands for
Enhanced Enantioselectivity. Influence
of Chiral Hemilabile Pendant Groups
Aibin Zhang and T. V. RajanBabu*
Department of Chemistry, 100 West 18th AVenue, The Ohio State UniVersity,
Columbus, Ohio 43210
rajanbabu.1@osu.edu
Received March 16, 2004
ABSTRACT
C -Symmetric P-(2-X-aryl)-2,5-dialkylphospholanes (X ) dioxolan-2-yl or dioxan-2-yl), designed on the basis of a working model for asymmetric
2
induction, are effective ligands for the Ni(II)-catalyzed asymmetric hydrovinylation of styrenes. Excellent yields (>99%), selectivities for the
desired 3-arylbutenes (>99%), high S/C ratios (>1200), and ee’s (up to 91%) have been realized for a number of prototypical vinylarenes. In the
dioxolane series, the selectivity depends on the configuration of the C and C carbons.
4
5
Use of chiral monophosphines as ligands goes back to some
of the first discoveries in asymmetric catalysis. In 1968,
Horner,1a Knowles,1b and their co-workers showed that
replacement of Ph3P in Wilkinson-type Rh-complexes pro-
duced asymmetric catalysts that gave varying degrees of
selectivity in hydrogenation reactions. The enantioselectivi-
ties in these initial studies remained low, and interests in
monophosphines as chiral ligands saw only sporadic interest
until recently.2 Many reactions failed to proceed, or gave
unacceptably low enantioselectivities when bidentate ligands
were employed. In one such example, we reported that
bidentate phosphines inhibited the Ni(II)-catalyzed het-
erodimerization of ethylene and vinylarenes (step 1, Scheme
1).3 We showed that catalytic activity can be fully restored
Scheme 1. Asymmetric Hydrovinylation and Synthesis of
2-Arylpropionic Acids
with a phosphine, carrying a hemilabile group at the optimum
site (Table 1).4 Anecdotal evidence by way of the effect of
variations of this hemilabile group, of its synergistic relation
to various counterions, and NMR spectroscopy of the
(1) (a) Horner, L.; Siegel, H.; Bu¨the, H. Angew. Chem., Int. Ed. Engl.
1968, 7, 942. (b) Knowles, W. S.; Sabacky, M. J. J. Chem. Soc., Chem.
Commun. 1968, 1445.
(2) (a) For recent reviews dealing with this topic, see: (a) Lagasse, F.;
Kagan, H. B. Chem. Pharm. Bull. 2000, 48, 315. (b) Hayashi, T. Acc. Chem.
Res. 2000, 33, 354. (c) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346. (d)
Komarov, I. V.; Bo¨rner, A. Angew. Chem., Int. Ed. 2001, 40, 1197. (e) For
a compilation of more recent references, see, Colby, E. A.; Jamison, T. F.
J. Org. Chem. 2003, 68, 156.
(3) (a) Nomura, N.; Jin, J.; Park, H.; RajanBabu, T. V. J. Am. Chem.
Soc. 1998, 120, 459. (b) RajanBabu, T. V.; Nomura, N.; Jin, J.; Nandi, M.;
Park, H.; Sun, X. J. Org. Chem. 2003, 68, 8431. (c) RajanBabu, T. V.
Chem. ReV. 2003, 103, 2845.
(4) For use of hemilabile ligands in related reactions, see: Meking, S.;
Keim, W. Organometallics 1996, 15, 2650 and references therein.
10.1021/ol0495063 CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/31/2004

Table 1. Effect of Bidentate and Hemilabile Ligands in
Table 2. Asymmetric Hydrovinylation of 4-Isobutylstyrene
Hydrovinylation
a Selectivity for 3-arylbutene.
intermediates [(allyl)Ni+P X-] suggested the possibility that
variation in this group could lead to an improvement of the
selectivity in the asymmetric hydrovinylation reaction.5 Even
though use of ligands with chiral side chains has been
reported before,6 there is no explicit mention of the use of
this as a control element in asymmetric catalysis. As a test
case, we chose a commercially relevant substrate, 4-isobu-
tylstyrene, for which the best selectivity reported to date has
been only 74%.7,8 Our expectations of higher selectiVity and
efficiency have been met. Details of these studies are reported
in this paper.
Based on a working model9 for asymmetric induction in
this reaction (Figure 1), we decided to examine the effect of
a Selectivity for 3-arylbutene. b The rest are cis- and trans-2-aryl-2-
butenes.
2,5-dialkylphospholanes (X ) dioxan-2-yl or dioxalan-2-yl,
Table 2) via modification of a procedure published earlier
(Scheme 2).5,10
Scheme 2. Synthesis of a Prototypical Phospholane/Acetal
Ligand 1a
Figure 1. Working model for asymmetric induction in the
hydrovinylation reaction.
a Key: (RR)-butane-2,3-diol, H+; (b) HP(O)(OEt)2/Pd(OAc)2,
dppb, EtNPri2, DMSO, 100 °C; (c) LAH/THF.
introducing additional elements of chirality at the hemilabile
position. We prepared a series of C2-symmetric P-(2-X-aryl)-
In scouting experiments, the hydrovinylation reaction was
carried out using 0.007 equiv of Ni and the phosphine ligand
in an atmosphere of ethylene at -55 °C.10 The results are
tabulated in Table 2. The acetal-containing phospholanes (1-
(5) Nandi, M.; Jin, J.; RajanBabu, T. V. J. Am. Chem. Soc. 1999, 121,
9899.
(6) For selected examples of monophosphines with chiral side chains,
see: (a) Hayashi, T.; Hayashizaki, K.; Kiyoi, T.; Ito, Y. J. Am. Chem. Soc.
1988, 110, 8153. (b) Reetz, M. T.; Mehler, G. Angew. Chem., Int. Ed. 2000,
39, 3889. (c) Also see refs 2c and 3b. Many examples of the effects of
chirality of one or other atom of a chelating ligand are known. For a recent
example, see: Shintani, R.; Fu, G. C. Org. Lett. 2002, 4, 3699.
(7) Park, H.; RajanBabu, T. V. J. Am. Chem. Soc. 2002, 124, 734.
(8) Feringa’s phosphoramidites, a class of BINAPO-derived ligands
useful for asymmetric hydrovinylation, give only a low yield of the product
(28% yield, 68% ee) in the hydrovinylation of 4-isobutylstyrene. Francio´,
G.; Faraone, F.; Leitner, W. J. Am. Chem. Soc. 2002, 124, 736.
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Org. Lett., Vol. 6, No. 9, 2004

5), in general, are excellent ligands for asymmetric hydro-
vinylation, giving quantitative yields and selectivities for the
expected 3-arylbutenes.
amidites8 are known to give excellent ee’s for 4-halostyrenes.
Thus, the advantages of the new ligands are complementary
to the known ones with respect to substrates.
Finally, the catalytic efficiency of the reaction was
examined using ligand 1a. In a reaction carried out with
4-isobutylstyrene/Ni(II)1a ratio of 1428 (0.07 mol % catalyst)
a yield of 86% (rest, starting material) was realized (see the
equation below). Under these conditions, the enantioselec-
tivity was only 72%, a clear indication that further process
improvements will be needed for a practical synthesis of (S)-
ibuprofen by this route.
The combination of (SS)-2,5-dimethylphospholane and
acetal derived from (RR)-2,3-butanediol (1a) gives the best
selectivity (91%ee, entry 1). Increasing the size of the
phospholane 2,5-substituents from Me to Et (1b) has a small
effect on ee, but significantly, this results in a slower reaction
(entry 1). A change in chirality of the 4,5-carbons of the
1,3-dioxalane (2, entry 2) leads to onset of isomerization of
the primary product (up to 10%) and significant deterioration
of the enantioselectivity (71% ee).10 Most notably, the ligand
3, with an achiral acetal appendage, gives selectivity between
that of the two diastereomers 1a and 2 (entry 3). Structurally
analogous ligands 4 and 5 with 1,3-dioxane side-chain behave
in a similar fashion. In this case, as expected, the (RR)-
phospholane/(SS)-dioxane combination (5) gives the best
results (entry 5). An examination of the results from entries
1-5 shows that the stereoselectivity of the reaction is dictated
by the chirality of the phospholane ring, with the (RR)-
phospholane favoring (S)-3-arylbutene, in accordance with
the proposed model.
Use of the ligand 1a in hydrovinylation of other vinylare-
nes gave the following ee’s under the typical reaction
conditions (0.70 mol % Ni/-55 °C, >99.5% yield, unless
specified otherwise): styrene (88); 4-methylstyrene (86);
4-bromostyrene (71); 4-methoxystyrene (73, 80% yield);
2-methoxy-6-vinylnaphthalene (86, 73% yield, 2.8 mol %
Ni). Except for 4-bromostyrene, these are among the highest
ee’s reported for the asymmetric hydrovinylation of these
substrates. Incidentally, diarylphosphinite7 and phosphor-
In conclusion, using a heuristic model for induction of
asymmetry in the hydrovinylation reaction, we have designed
a new set of hemilabile ligands that give among the best
ee’s and turnover numbers for this exacting reaction. These
ligands, and the principles envisioned in their design, may
find broader applications in asymmetric catalysis of reactions
where monophosphines are the only viable alternatives. We
are currently examining other applications of these ligands.
Acknowledgment. This paper is dedicated to Professor
Leo A. Paquette in recognition of his numerous scientific
and other contributions to organic chemistry. Financial
assistance for this research by US National Science Founda-
tion (CHE-0308378) and the Petroleum Research Fund of
the ACS (36617-AC1) is gratefully acknowledged.
(9) This model assumes the involvement of diastereomeric (phosphorus/
olefin) cis and trans square planar transition states for the Ni-H addition
to the prochiral faces of the olefin. While the cis-P/olefin complex appears
to have a clear choice for the re-face addition, for the trans P/olefin complex
there is no such preference. Our conjecture is that additional elements of
chirality at the hemilabile position would favor one or other of these addition
modes leading to increased selectivity.
(10) See the Supporting Information for full experimental details,
characterization, and analytical data including chromatographic traces of
products.
Supporting Information Available: Full experimental
details of various hydrovinylation reactions; spectroscopic
and chromatographic data for characterization of compounds
listed. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL0495063
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