Enantioselective palladium catalyzed allylic substitution with 2,2'- bipyridine ligands

Article abstract of DOI:10.1016/S0957-4166(97)00624-1

A number of chiral C₁-symmetric 2,2'-bypyridines were prepared and assessed in the enantioselective palladium catalyzed allylic substitution of 1.3-diphenylprop-2-enyl acetate with dimethylmalonate. Enantioselectivity up to 89% was obtained.

Full text of DOI:10.1016/S0957-4166(97)00624-1

Pergamon
Tetrahedron: Asymmetry 9 (1998) 531–534
Enantioselective palladium catalyzed allylic substitution with
2,20-bipyridine ligands
Giorgio Chelucci,a,∗ Gerard A. Pinna b and Antonio Saba a
aDipartimento di Chimica, Universitità di Sassari, Via Vienna 2, I-07100 Sassari, Italy
bIstituto di Chimica Farmaceutica, Università di Sassari, Via Muroni 23, I-07100 Sassari, Italy
Received 6 November 1997; accepted 8 December 1997
Abstract
A number of chiral C1-symmetric 2,20-bypyridines were prepared and assessed in the enantioselective palladium
catalyzed allylic substitution of 1,3-diphenylprop-2-enyl acetate with dimethylmalonate. Enantioselectivity up to
89% was obtained. © 1998 Elsevier Science Ltd. All rights reserved.
Enantioselective reactions based on palladium catalyzed allylic substitutions are currently an actively
pursued research area.1 In this context a number of nitrogen ligands are now reaching high levels of
stereocontrol.1,2
Recently, continuing our interest in the synthesis and application of chiral pyridine derivatives as
ligands for metal complexes in enantioselective catalysis,3 we have evaluated the potential utility of
a number of chiral ligands with sp2-nitrogen donors as chiral controllers for enantioselective palla-
dium catalyzed allylic substitutions.4 This preliminary investigation indicated that C1-symmetric 2,20-
bipyridines were able to provide active palladium catalysts and that the use of the related bipyridines
with C2-symmetry was detrimental for both the catalytic activity and stereoselectivity of the reaction.
The best enantioselectivity (32% ee) was obtained with the ligand 1, while with 2 the process was not
enantioselective.
These promising results prompted us to prepare and assess in this catalytic process C1-symmetric
bipyridines in which the substituents on the stereocentre bonded to the heterocyclic ring are arranged in
a rigid backbone in such a way as to provide a more rigid array of the ligand around the metal centre.
∗
Corresponding author. E-mail: chelucci@ssmain.uniss.it
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(97)00624-1

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G. Chelucci et al. / Tetrahedron: Asymmetry 9 (1998) 531–534
In this paper we report the application of a number of chiral 2,20-bipyridines derived from 6,6-
dimethyl-5,7-methano-2-(2-pyridinyl)-5,6,7,8-tetrahydroquinoline 45 in the enantioselective palladium
catalyzed allylic substitution of 1,3-diphenylprop-2-enyl acetate with dimethylmalonate.
The ligands 5–7 were prepared from the bipyridine 4,6 readily accessible by reaction of (+)-
pinocarvone 36 with 1-phenacylpyridinium iodide5 (Scheme 1). The red solution of lithiated 4, obtained
by treatment with lithium diisopropylamine (LDA) at −40°C for 3 h and then 1 h at 0°C, was quenched
with the proper alkyl halide to give ligands 5a–c.7,8 To obtain the ligands 6 and 7 lithiated 4 was quenched
with acetone and then the obtained carbinol 5d6 was converted into the corresponding methyl ether
67 and trimethylsilyl ether 77 with sodium hydride/methyl iodide and imidazole/trimethylsilyl chloride,
respectively
Scheme 1.
To test the ability of these new ligands to provide asymmetric induction in the palladium-catalysed
allylic substitutions we examined the alkylation of 1,3-diphenylprop-2-enyl acetate with dimethyl mal-
onate. Allylic substitutions were carried out employing Trost’s procedure which used [Pd(η3-C3H5)Cl]2
as procatalyst and a mixture of dimethyl malonate, N,O-bis(trimethylsilyl)acetamide (BSA) and potas-
sium acetate.9 The reactions were carried out in methylene chloride at room or at reflux temperature. The
results of the catalytic reaction are reported in Table 1.
2,20-Bipyridines 4–7 were able to provide effective palladium catalysts. Total conversion of the starting
material was achieved with these ligands in less than 48 h at room temperature to give high yields of
dimethyl 1,3-diphenylprop-2-enylmalonate 9. Only the reaction employing 7 proceeded much slower
than those with the other ligands and was complete in 12 days.
The effect of the introduction of alkyl groups at the 8-position of the tetrahydroquinoline ring of 4
was dramatic for the stereoselectivity and reaction rate of the process. The best stereoselectivity (89%
ee) was obtained with the 8-benzyl substituted ligand 5b. Unexpectedly, the bipyridine 6 bearing the
crowded C(CH3)2OCH3 group gave a stereoselectivity and reaction rate similar to that of unsubstituted
bipyridine 4. With the bipyridine 7, bearing the very sterically demanding C(CH3)2OSi(CH3)3 group,
a dramatic drop of the catalytic activity was observed and the stereochemical outcome was inverted.
Indeed, while in all cases the absolute configuration of the substitution product 9 was controlled by the
absolute configuration at the stereogenic centre at the 8-position of tetrahydroquinoline ring, resulting in
the preferred formation of (R)-9, in this case 9 was obtained with (S)-configuration. This stereochemical
result is probably due to this ligand being too sterically crowded to enable effective coordination to
palladium. Therefore, in this case the reactive transition states could be different from those of the others
ligands.
Finally, it should be noted that the 8-unsubstituted bipyridine 4 gave a much lower enantiomeric excess

G. Chelucci et al. / Tetrahedron: Asymmetry 9 (1998) 531–534
533
Table 1
Allylic alkylation of 1,3-diphenylprop-2-enyl acetate with dimethyl malonatea
than the 8-substituted bipyridine 5 but the same sense of enantioselection. This stereochemical result
reasonably indicates that in bipyridine 5 the stereocentre at the 8-position and those at the 5,7-positions
are not in a mismatching relation.
Very good results in palladium catalysed allylic substitutions have been achieved using a C2-symmetric
as well as C1-symmetric nitrogen-containing ligands.1 The origin of the selectivity, however may be
different with the two types of ligands. Considering palladium catalysed allylic substitutions, which
proceed through a meso η3-allyl intermediate, the accepted mechanism foresees that the nucleophile
attacks at the allylic termini of two alternative diastereomeric π-allyl palladium complexes. The regio-
selectivity and stereoselectivity of the nucleophilic attack is determined by steric and electronic properties
of the ligand. While steric factors may be controlled with C2-symmetric ligands, electronic factors may
be more easily controlled with C1-symmetric ligands in which two different donor atoms (such as in
phosphinooxazolines,10 thiophenooxazolines11 and phosphinoamines12 ) or two identical atoms insert in
different surroundings (such as the nitrogen atoms in aminopyridines,13 pyridyloxazolines14 ) may be
chosen.
We have now found that C1-symmetric 2,20-bipyridines, ligands which don’t possess such a require-
ment (the electronic properties of the nitrogen atoms of the two pyridine rings are nearly identical) are
able to give very good enantioselectivity in palladium catalysed allylic substitutions. Therefore these
results contribute to the understanding of which factors are important for the palladium catalysed allylic
alkylation.

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G. Chelucci et al. / Tetrahedron: Asymmetry 9 (1998) 531–534
References
1. Trost, B. M.; Van Vranken, D. L. Chem. Rev., 1996, 96, 395. Reiser, O. Angew. Chem., 1993, 105, 576; Angew. Chem.
Int. Ed. Engl., 1993, 32, 547. Hayashi, T. In Catalytic Asymmetric Synthesis, Ed. Ojima, VCH, Weinheim, 1993. Frost, C.
G.; Howarth, J.; Williams, J. M. J. Tetrahedron: Asymmetry, 1992, 3, 1089. Dawson, G. J.; Williams, J. M. J.; Coote, S. J.
Tetrahedron: Asymmetry, 1995, 2535, and references therein.
2. Togni, A.; Venanzi, L. M. Angew. Chem. Int. Ed. Engl., 1994, 33, 497.
3. Chelucci, G.; Marchetti, M.; Sechi, B. J. Mol. Catal., 1997, 122, 111. Chelucci, G.; Berta, D.; Saba, A. Tetrahedron, 1997,
53, 3843. Chelucci, G. Tetrahedron: Asymmetry, 1997, 8, 2667 and references therein.
4. Chelucci, G.; Caria, V.; Saba, A. J. Mol. Catal., 1997, in press.
5. Havoz, P.; von Zelewsky, A. Tetrahedron Lett., 1992, 33, 5165.
6. Compound 4: mp 80–81°C; [α]25 +97.46 (c 2.6, CHCl3). We prepared compound 3 by MnO2 oxidation of (−)-trans-
D
pinocarveol (Fluka A. G.).
7. All compounds showed satisfactory spectroscopic and analytical data. Compounds 5a–c: Chen et al.8 Compound 5d was
isolated in 89% yield after chromatographic purification on Al2O3 (petroleum ether:ethyl ether=1:1): mp 122–3°C; [α]25
D
−26.2 (c 2.3, CHCl3); 1H NMR (CDCl3): δ 8.65 (d, 1H), 8.20 (d, 1H), 8.07 (s, 1H), 7.78 (t, 1H), 7.42 (d, 1H), 7.28 (m,
1H), 3.28 (s, 1H), 2.81 (t, 1H), 2.62 (m, 1H), 2.38 (d, 1H), 1.86 (s, 1H), 1.45 (s, 3H), 1.42 (d, 1H), 1.36 (s, 3H), 1.12 (s, 3H),
0.71 (s, 3H). Compound 6 was isolated in 83% yield after flash chromatography (petroleum ether:ethyl acetate): oil, [α]25
D
+48.0 (c 1.4, CHCl3); 1H NMR (CDCl3): δ 8.64 (d, 1H), 8.38 (d, 1H), 8.13 (d, 1H), 7.79 (t, 1H), 7.32 (d 1H), 7.24 (m, 1H),
3.65 (s, 1H), 3.23 (s, 3H), 2.75 (m, 1H), 2.61 (m, 1H), 1.85 (s, 3H), 1.60 (d, 1H), 1.45 (s, 3H), 1.36 (d, 1H), 1.23 (s, 3H),
0.62 (s, 3H). Compound 7: was isolated in 95% yield after chromatographic purification on Al2O3 (petroleum ether:ethyl
acetate=7:3): mp 121–122; [α]25D −44.8 (c 2.0, CHCl3); 1H NMR (CDCl3): δ 8.62 (d, 1H), 8.36 (d, 1H), 8.12 (d, 1H), 7.75
(t, 1H), 7.26 (d, 1H), 7.22 (m, 1H), 3.07 (s, 1H), 2.70 (m, 1H), 2.66 (m, 1H), 2.49 (m, 1H), 1.79 (d, 1H), 1.71 (s, 3H), 1.53
(s, 3H), 1.42 (s, 3H), 0.58 (s, 3H), 0.08 (s, 9H).
8. Chen, C.; Tagami, K.; Kishi, Y. J. Org. Chem., 1995, 60, 5386.
9. Trost, B. M.; Murphy, D. J. Organometallics, 1985, 4, 1143.
10. von Matt, P.; Pfaltz, A. Angew. Chem. Int. Ed. Engl., 1993, 32, 556. Sprinz, J.; Helmchen, G. Tetrahedron Lett., 1993, 34,
1767. Dawson, G. J.; Frost, C.; Williams, J. M. J.; Coote, S. J. Tetrahedron Lett., 1993, 34, 3149.
11. Allen, V. J.; Bower, J. F.; Williams, J. M. J. Tetrahedron: Asymmetry, 1994, 5, 1895.
12. Trost, B. M.; Breit, B.; Peukert, S.; Zambrano, J.; Ziller, J. W. Angew. Chem. Int. Ed. Engl., 1995, 34, 2386. Trost, B. M.;
Van Vranken, D. L. Angew. Chem. Int. Ed. Engl., 1992, 31, 228.
13. Chelucci, G.; Pinna, G. A.; Saba, A. Tetrahedron: Asymmetry, 1997, 8, 2571.
14. Nordström, K.; Macedo, E.; Moberg, C. J. Org. Chem., 1997, 62, 1604. Chelucci, G.; Medici, S.; Saba, A. Tetrahedron:
Asymmetry, 1997, 8, 3183.