New chiral phosphinooxathiane ligands for palladium-catalyzed asymmetric allylic substitution reactions

Article abstract of DOI:10.1016/S0040-4039(00)00674-2

New chiral ligands, phosphinooxathianes 3 and 6, were synthesized easily and their ability as ligands were examined in Pd-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate to give an allylation product. Enantiomeric excess of up to 94% has been obtained using 1 mol% of [PdCl(η³-C₃H₅)]₂ and 2 mol% of 3. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00674-2

Tetrahedron Letters 41 (2000) 4615±4618
New chiral phosphinooxathiane ligands for palladium-
catalyzed asymmetric allylic substitution reactions
Hiroto Nakano,* Yuko Okuyama and Hiroshi Hongo*
Tohoku Pharmaceutical University, Aoba-ku, Sendai 981, Japan
Received 15 March 2000; accepted 21 April 2000
Abstract
New chiral ligands, phosphinooxathianes 3 and 6, were synthesized easily and their ability as ligands
were examined in Pd-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate with
dimethyl malonate to give an allylation product. Enantiomeric excess of up to 94% has been obtained
using 1 mol% of [PdCl(Z3-C3H5)]2 and 2 mol% of 3. # 2000 Elsevier Science Ltd. All rights reserved.
During the last decade, several ecient enantioselective catalysts have been explored for the
Pd-catalyzed asymmetric allylic substitutions.1 However, oxathianes are not popular as a chiral
ligand and have not been involved so far in this area. To the best of our knowledge, oxathianes
have been used only in the asymmetric carbonyl epoxidation.2 In this communication, we wish to
report the synthesis of a new type of two chiral ligands, norbornane-based phosphinooxathiane 3
and pulegone-based phosphinooxathiane 6, followed by the application to Pd-catalyzed allylic
alkylation. This is the ®rst example that uses oxathianes as a chiral ligand to Pd-catalyzed asymmetric
allylic substitutions.
Preparations of the chiral ligands 3 and 6 are described in Scheme 1. The chiral norbornane-
based phosphinooxathiane 33 was readily synthesized in 92% yield by the condensation of com-
mercially available (1S)-(^)-10-mercaptoisoborneol 1 with 2-(diphenylphosphino)benzaldehyde 2
in re¯uxing toluene using a Dean±Stark apparatus. In addition, this reaction gave the ligand 3 in
82% yield with 7% yield of the diastereomer 44 when benzene was used as a solvent. (+)-Pulegone-
based phosphinooxathiane 64 was obtained from the hydroxy thiol (a diastereomeric mixture of
which the major component 5 constitutes 82% as indicated by 13C NMR)5 with 2 in re¯uxing
toluene. The stereochemistries of the newly created stereogenic center at the a-position of the 1,3-
1
oxathiane ring for 3 and 6 were determined by the NOE measurement of H NMR spectra,
respectively. Thus, the NOE experience for 3 and 6 con®rmed an interaction between the hydrogen
at the a-position and at the b-position, respectively.
* Corresponding authors. Tel:+81 22 234 4181; fax:+81 22 275 2013; e-mail: hnakano@tohoku-pharm.ac.jp
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00674-2

4616
Scheme 1.
In order to examine the e€ectiveness of the ligands, the enantioselective allylic alkylation of
1,3-diphenyl-2-propenyl acetate 7 with dimethyl malonate was tried in the presence of p-allyl-
palladium chloride dimer to give allylation product 8. The results are summarized in Table 1. The
reactions were tried under the BSA standard conditions (entries 1±10). When the reactions were
carried out at room temperature and 0ꢀC by using 1 mol% [PdCl(Z3-C3H5)]2 and 2 mol% ligand
3, respectively, outstanding results were not obtained for the enantiomeric excesses (ee) (rt: 89%
ee, 0ꢀC: 91% ee), although the reactions proceeded fast and in good chemical yields (rt: 96%,
0ꢀC: 75%) (entries 1 and 2). A satisfactory result (80% and 94% ee) was achieved by using 1
mol% [PdCl(Z3-C3H5)]2 and 2 mol% ligand 3 at ^30ꢀC for 24 h (entry 3).6 The same enantio-
meric excess (94% ee) was obtained at ^50ꢀC, although the chemical yield was moderate (62%)
(entry 4). The same reaction at ^78ꢀC gave the product 8 in quite low chemical yield (13%) (entry
5). High enantiomeric excess (93% ee) was con®rmed when toluene was used as a solvent, but the
chemical yield was not good (entry 6). The condition using tetrabutylammonium ¯uoride (TBAF)
gave 39% and 88% ee (entry 7). The reaction was tried by using 0.5 mol% [PdCl(Z3-C3H5)]2 and
1 mol% ligand 3 under the same reaction conditions of entry 3 (entry 8). However, these reaction
conditions did not give any better result in comparison with entry 3. Next, we tested the e€ec-
tiveness of the chiral ligands 4 and 6, and found, both 4 and pulegone-based phosphinooxathiane
6 were less e€ective under these reaction conditions (entries 9 and 10). From the above results, it
is seen that phosphinooxathiane 3 is an excellent ligand in this allylation under the reaction
conditions of entry 3. Futhermore, we examined the regio- and stereoselective allylation of
cinnamyl acetate 9 with dimethyl malonate in the presence of the chiral ligand 3 and the palladium
catalyst.1e,g i The reactions when performed at rt and ^30ꢀC for 24 h in CH2Cl2 using 1 mol%
[PdCl(Z3-C3H5)]2 and 2 mol% ligand 3 (entries 11 and 12) proceeded to give almost quantitative
yields. However, the regioselectivity for branched product 10 was not high (rt: 10/11=25/75,
^30ꢀC: 10/11=20/80) and the enantioselectivity of 10 was at a moderate level (61% ee) at ^30ꢀC
(Table 1).

4617
Table 1
Asymmetric Pd-catalyzed allylation of acetates 7 and 9
Scheme 2.

4618
It is considered that the enantiodi€erentiation step in Pd-catalyzed allylation is the substitution
of p-allyl complexes with nucleophiles, and nucleophilic attack occurs predominantly at the allyl
terminus from trans to the better p-acceptor (P>>S).7 Since the (R) product was obtained as the
major enantiomer, the reaction probably proceeds through an M-type A rather than a W-type B
intermediate.7 In addition, the di€erentiation of chemical yields and enantiomeric excesses for
ligands 3 and 6 may be explained by steric inferences. Thus, ligand 6 has a bulky gem-dimethyl
group in the oxathiane ring that obstructs the construction of the p-allyl palladium complex C
(Scheme 2).
In conclusion, we have prepared two kinds of new chiral ligands 3 and 6. Particularly, 3 was a
good and e€ective ligand for allylic substitution reactions to give excellent chemical yield and
enantiomeric excess. Further applications and modi®cations of the ligand 3 are in progress.
References
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C29H31OPS: C, 72.95; H, 6.81. Found: C, 72.65; H, 6.53. MS m/z: 458 (M+).
4. 1H NMR data of ligands 4 and 6: Compound 4: ꢁ (CDCl3): 7.82 (m, 1H), 7.15±7.43 (m, 11H), 6.91 (m, 1H), 5.81
(d, J=9.2 Hz, 1H), 3.77 (m, 1H), 2.80 (d, J=11.2 Hz, 1H), 2.33 (d, J=11.2 Hz, 1H), 1.57±1.78 (m, 2H), 1.18±1.44
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7.17 (t, J=7.4 Hz, 1H), 6.89 (m, 1H), 6.61 (d, J=8.2 Hz, 1H), 3.39 (t, J=10.1 Hz, 1H), 1.82 (m, 1H), 1.66±1.79
(m, 2H), 1.50 (m, 1H), 1.36 (s, 3H), 1.19 (s, 3H), 1.10 (q, J=12.2 Hz, 1H), 0.87 (d, J=6.6 Hz, 1H), 0.86 (m, 1H).
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C3H5)]2 (1.46 mg, 0.004 mmol) in dry dichloromethane (1 ml) was stirred at room temperature for 1 h and the
resulting yellow solution was added to a mixture of acetate 7 (100 mg, 0.4 mmol) and potassium acetate (0.8 mg,
0.008 mmol) in dry dichloromethane (1 ml) using a syringe followed by the addition of dimethyl malonate (160
mg, 1.2 mmol) and BSA (244 mg, 1.2 mmol). The reaction was carried out at ^30ꢀC for 24 h and the reaction
mixture was diluted with ether and was quenched with satd NH4Cl. The organic layer was washed with brine and
dried over MgSO4. The solvent was evaporated under reduced pressure and the residue was puri®ed by
preparative TLC (hexane:ether=5:1) to give a pure product 8.1a,b The enantiomeric excess was determined by
HPLC (Chiralcel OD-H, 0.5 ml/min, hexane:2-propanol=98:2).
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