Highly active catalysts of bisphosphine oxides for asymmetric Heck reaction

Article abstract of DOI:10.1039/c3cc45233f

Bisphosphine oxides formed highly active asymmetric Heck catalysts, which were applied in asymmetric synthesis of pharmacologically active azacycles. Olefin insertion proceeded via cis pathways, different from P,N-ligands.

Full text of DOI:10.1039/c3cc45233f

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Highly active catalysts of bisphosphine oxides for
asymmetric Heck reaction†
Cite this: DOI: 10.1039/c3cc45233f
Jian Hu, Yunpeng Lu, Yongxin Li and Jianrong (Steve) Zhou*
Received 11th July 2013,
Accepted 13th August 2013
DOI: 10.1039/c3cc45233f
www.rsc.org/chemcomm
Bisphosphine oxides formed highly active asymmetric Heck catalysts, limitation, intermolecular asymmetric Heck reaction was rarely
which were applied in asymmetric synthesis of pharmacologically used in synthesis.6 Herein, we report that bisphosphine oxide
active azacycles. Olefin insertion proceeded via cis pathways, different catalysts based on a spiro backbone can form highly active Heck
from P,N-ligands.
catalysts (Fig. 1c).
Initially, we examined Heck reaction of cyclopentene and
In 1991, Hayashi et al. reported the first example of asymmetric ArOTf using a combination of Pd(dba)2 and BINAP as a catalyst
Heck reaction and 2,3-dihydrofuran, a highly active olefin, was precursor (Fig. 2a). In dry 1,4-dioxane, only low catalytic activity
used as the olefin substrate. It was noticed that the majority of and low ee were observed. When water was included as a minor
initial Heck products underwent C–C double bond migration cosolvent, the coupling became surprisingly faster and the ee and
(Fig. 1a).1 Since then, the reaction has become a testing ground olefinic selectivity ‘‘s’’ also dramatically improved over time.
for chiral phosphorus ligands.2 For example, Pfaltz’s PHOX ligand
We suspected that (R)-BINAP was in situ oxidized to form its
can minimize the double-bond isomerization. However, its turn- oxide, (R)-BINAP(O), which was more active and stereoselective.7
over was very slow and often days were needed to realize full
conversion (Fig. 1b).3 So far many structural variants of bisphos-
phites, mixed oxazoline–phosphines4 and bisphosphines5 have
been tested, but good ee was mostly limited to simple olefins
such as 2,3-dihydrofuran and cyclopentene. A general method
that is applicable to various olefins was lacking. Because of this
Fig. 1 Examples of asymmetric Heck reactions.
Division of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link,
Singapore 637371. E-mail: jrzhou@ntu.edu.sg; Fax: +65 67911961
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization. CCDC 932284. For ESI and crystallographic data in CIF or
Fig. 2 Catalyst discovery.
other electronic format see DOI: 10.1039/c3cc45233f
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Fig. 4 Asymmetric syntheses of chiral azacyclic drugs.
(R)-Xyl-SDP(O) can be successfully applied to various aryl triflates
in coupling with cyclopentene and 2,3-dihydrofuran (Fig. 3a and b).
Some vinyl and heteroaryl triflates also coupled well.
Moreover, some other olefins also coupled well with 1-naphthyl
triflate (Fig. 3c). (R)-Xyl-SDP(O) gave only 83% ee in the reaction
of cyclohexene, the least reactive olefin. Modification of both
phosphine substituents improved the ee to 93% (Fig. 3d).
Without its fluorine atom, the catalytic activity was much lower.
Another six-membered olefin, 3,4-dihydropyran, also reacted in
excellent ee. Unfortunately, no Heck reaction occurred between
PhOTf and cyclohexene.14
Aryl-substituted azacycles of piperidines and pyrrolidines are
commonly used in drug discovery. We have prepared two drug
candidates (Fig. 4). One example is preclamol. The catalyst loading
can be lowered to 0.1 mol%. Ozonolysis and ring closing amination
gave (+)-preclamol in 96% ee.15 Its enantiomer was promising for
the treatment of schizophrenia.16 Another example is BMS-394136,
which was developed to treat cardiac arrhythmia or irregular
heartbeat.17 Heck reaction can quickly provide 2-arylpyrrolidine
in 98% ee. 3 steps were needed to assemble the azacycle via
Rh-catalyzed arylation of N-tosylimine.18
Fig. 3 Heck reaction of various olefins.
When isolated (R)-BINAP(O) was tested as a ligand, the result was
indeed much better,8 which gave 97% ee and >40 : 1 olefinic
selectivity (Fig. 2a).9 Similarly good results were obtained in
1,4-dioxane solvent. BINAP dioxide was unreactive.
Unfortunately, in many cases of ArOTf, (R)-BINAP(O) gave
o90% ee. For example, ArOTf bearing a para-ester group
provided 88% ee (Fig. 2b). When some BINAP oxide analogues
were tested, not much improvement was observed. Both seg-
phos and difluorphos oxides were unsatisfactory. Eventually,
we found that a bisphosphine oxide having a 1,10-spirobiindane
skeleton was the best choice.10 (R)-Xyl-SDP(O) gave 97% ee and 26 : 1
olefin selectivity.11 Notably, (R)-SDP(O) and (R)-BINAP(O) ligands
gave mirror images of Heck products. The two ligands are techni-
cally pseudoenantiomers due to different nomenclature of axial and
spiro chiralities. The bisphosphine oxides are poorer s-donors
than bisphosphines on Pd. On more electron-deficient cationic
Pd centers, olefin insertion is faster and the deprotonation of
Pd hydride species by bases is also faster. Fast deprotonation is
critical to regenerate Pd0 catalysts12 and to minimize double bond
migration.13
Fig. 5 (a) Synthesis of cis-complex A {[(R)-Xyl-SDP(O)](p-CF3-phenyl)(I)PdII} and
(b) stoichiometric reaction of 2,3-dihydrofuran.
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We thank the Singapore National Research Foundation
(NRF-RF2008-10) and Nanyang Technological University for
financial support. We thank Johnson Matthey for a gift of
palladium.
Notes and references
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Fig. 6 Left: ORTEP diagram of cis-complex A {[(R)-Xyl-SDP(O)](p-CF3-phenyl)(I)PdII}
with 50% thermal ellipsoid probability and hydrogen omitted for clarity. Right:
front view of complex A with the bisphosphine oxide in space-filling style.
3 (a) O. Loiseleur, P. Meier and A. Pfaltz, Angew. Chem., Int. Ed. Engl.,
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Fig. 7 Calculated transition states, TS(a) (left) and TS(b) (right), for 2,3-dihydro-
furan insertion into cationic cis-complex {[(R)-Xyl-SDP(O)](p-CF3-phenyl)PdII}. The
B3LYP method was used and a polarizable continuum model accounted for the
solvent effect in 1,4-dioxane.
We were curious about the origin of excellent ee induced by
bisphosphine oxide catalysts. A neutral complex A was prepared
from (R)-Xyl-SDP(O), Pd2(dba)3 and aryl iodide (Fig. 5). Subse-
quent treatment of complex A with 2,3-dihydrofuran gave the
desired Heck product in 98% ee in the presence of AgOTf, a
halide abstractor.
X-ray diffraction analysis of complex A showed that the
bisphosphine monoxide ligand was bonded to Pd in a k-P,O
mode (Fig. 6).19 Notably, the Pd-bound aryl and phosphine
groups were cis to each other to form a so-called cis complex.
Next, we used the DFT method to calculate the olefin inser-
tion step, starting from a cationic cis {[(R)-Xyl-SDP(O)](phenyl)-
(2,3-dihydrofuran)Pd} (Fig. 7). The k-P,O binding mode of the
chiral ligand was preserved during calculations. Alternative
monodentate binding mode or k-P,C mode involving a palladium–
arene interaction was found to be much less stable. Transition state
TS(a) leading to the experimentally observed (2S)-isomer was found
to be 2.6 kcal molꢀ1 lower in energy than TS(b). In TS(b), close
contact between the olefin and the phosphine oxide moiety was
7 F. Ozawa, A. Kubo and T. Hayashi, Chem. Lett., 1992, 2177.
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ˆ ´
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9 While our work was ongoing, Oestreich et al. reported the use
of BINAP(O) in asymmetric Heck reaction. The reaction of PhOTf
¨
and cyclopentene gave 86% ee: T. H. Woste and M. Oestreich,
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10 J.-H. Xie and Q.-L. Zhou, Acc. Chem. Res., 2008, 41, 581.
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from Zonebanner Jiuzhou Co., China.
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14 We tried Heck reaction of PhOTf and cyclohexene using the
tBu-PHOX ligand on the 0.1–0.5 mmol scale (ref. 3). The Heck
product was formed in low yield and the main side reaction was
reduction of PhOTf.
15 Previous synthesis of racemic preclamol: I. K. Bu¨chner and P. Metz,
Tetrahedron Lett., 2001, 42, 5381.
seen. When the trans pathways were investigated, the trans ground 16 (a) U. Hacksell, L. E. Arvidsson, U. Svensson, J. L. G. Nilsson,
states were 7–9 kcal molꢀ1 higher in energy than cis complexes,
depending on the orientation of the olefin. The trans complexes
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were destabilized by trans positioning of two strongly s-donating
phosphine and anionic aryl groups. In addition, the trans pathway
will lead to the ‘‘wrong’’ (2R)-isomer although energies of trans
transition states were similar to cis ones. Thus, the calculated cis
pathway was consistent with experimental results. The oxazoline–
phosphine catalysts were reported to operate via trans pathways.4d–f
J. Med. Chem., 1994, 37, 2735; (c) L. O. Hansson, N. Waters, S. Holm
and C. Sonesson, J. Med. Chem., 1995, 38, 3121.
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18 Z. Cui, H.-J. Yu, R.-F. Yang, W.-Y. Gao, C.-G. Feng and G.-Q. Lin,
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In conclusion, the bisphosphine oxides based on a spiro 19 BINAP(O) was ligated to arylpalladium(II) in the k-P,O mode:
W. J. Marshall and V. V. Grushin, Organometallics, 2002, 22, 555.
20 We recently reported Pd-catalyzed asymmetric intermolecular cycli-
backbone can form highly active catalysts for asymmetric Heck
reaction.20 The new catalyst was applied to synthesis of some
zation using bisphosphine oxide catalysts: J. Hu, H. Hirao, Y. Li and
medicinally interesting azacycles.
J. Zhou, Angew. Chem., Int. Ed., 2013, 33, 8676.
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