Remote electronic control of the ligand in the enantioselective palladium-catalyzed allylic alkylation with chiral oxazolinylpyridines

Article abstract of DOI:10.1016/S0957-4166(99)00116-0

New chiral oxazolinylpyridines bearing electron-donating and- withdrawing groups in the 4-position of the pyridine ring have been prepared and assessed in the enantioselective palladium catalyzed allylic substitution of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate. The electronic properties of substituents strongly affect the catalytic activity and only slightly affect the enantioselectivity of the substitution reaction. Enantioselectivity up to 93% was obtained.

Full text of DOI:10.1016/S0957-4166(99)00116-0

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1457–1464
Remote electronic control of the ligand in the enantioselective
palladium-catalyzed allylic alkylation with chiral
oxazolinylpyridines
Giorgio Chelucci,∗ Sebastiano P. Deriu, Antonio Saba and Raffaela Valenti
Dipartimento di Chimica, Università di Sassari, via Vienna 2, I-07100 Sassari, Italy
Received 22 February 1999; accepted 26 March 1999
Abstract
New chiral oxazolinylpyridines bearing electron-donating and withdrawing groups in the 4-position of the
pyridine ring have been prepared and assessed in the enantioselective palladium catalyzed allylic substitution of
1,3-diphenylprop-2-enyl acetate with dimethyl malonate. The electronic properties of substituents strongly affect
the catalytic activity and only slightly affect the enantioselectivity of the substitution reaction. Enantioselectivity
up to 93% was obtained. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Asymmetric induction with chiral metal-catalysts has been recognized as depending mainly on steric
repulsion (i.e. non-bonding interactions) between an active metal-center decorated by chiral ligands
and substrates. However, the chemo-, regio- and stereoselectivity in asymmetric catalytic reactions
can be determined not only by steric (steric control) but also by electronic properties of the ligand
(electronic control). Palladium-catalyzed asymmetric allylic substitution is a catalytic process in which
these concepts have found useful applications.1 The accepted mechanism for palladium-catalyzed allylic
substitutions which proceed through a meso η3-allyl intermediate, foresees that the nucleophile attacks
the allylic termini of two alternative diastereomeric π-allyl palladium complexes (C and D, Scheme 1).
As a consequence, there are, in principle, four main reaction pathways, of which two lead to product E
and the remainder to the other enantiomer ent-E. With ligands containing two coordination sites such
as phosphinooxazolines or thiophenooxazolines, while the steric properties of the ligand affect the ratio
at equilibrium between the intermediates C and D, the electronically different properties of the two
donor centers can control the approach of an incoming nucleophile on C or D. For instance, it has been
∗
Corresponding author. E-mail: chelucci@ssmain.uniss.it
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00116-0

1458
G. Chelucci et al. / Tetrahedron: Asymmetry 10 (1999) 1457–1464
demonstrated that in the allylic palladium–phosphinooxazoline complexes the nucleophile attacks the
carbon atom trans to the phosphane ligand (in Scheme 1: b in C and D if La=P and L=N) because this
group is a better π-acceptor than the nitrogen ligand and so it withdraws electron density trans to itself
making this carbon more susceptible to nucleophilic attack.2 Moreover, this electronic effect has been
increased in this class of ligands by making the Pd center more electrophilic, for instance by replacing
the phosphane substituent with a phosphite group.3
Scheme 1.
We have recently synthesized and assessed the palladium-catalyzed asymmetric allylic alkylations in
a number of chiral oxazolinylpyridines having different substituents on the pyridine and oxazoline rings
and we have disclosed their cross effects on the catalytic activity and stereoselectivity of the process
(steric control).4 Continuing our interest in this field,5 we have evaluated the possibility of electronically
controlling the catalytic process by differentiation of the electronic properties of the two very similar
oxazolinylpyridine nitrogens (electronic control) in order to synthesize oxazolinylpyridines in which
steric and electronic factors work together so as to optimize the asymmetric reaction. We thought that by
modifying the electron-donating properties of the pyridine nitrogen by the introduction on the pyridine
ring of electron-donating or withdrawing groups we could achieve this goal.6 Moreover, we decided to
synthesize oxazolinylpyridines where the electronic differentiating substituents are far from the catalytic
center, in order to differentiate the electronic effects from the steric effects.
We report here on the synthesis of chiral oxazolinylpyridines bearing electron-donating and with-
drawing groups in the 4-position of the pyridine ring and the results obtained with these ligands in the
palladium-catalyzed alkylation of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate.
2. Results and discussion
We have synthesized oxazolinylpyridines with a methoxy- or a chloro-group in the 4-position of the
pyridine ring and an iso-propyl- or phenyl-substituent on the oxazoline moiety (Scheme 2). Ligands
5c–f were prepared by heating a chlorobenzene solution of the corresponding cyanoheterocycles 3 and
4 under reflux with the appropriate aminoalcohol in the presence of a catalytic amount of zinc chloride7
(30–61% yields). Compounds 3 and 4 were obtained by oxidation of 1 and 2 with 3-chloroperbenzoic

G. Chelucci et al. / Tetrahedron: Asymmetry 10 (1999) 1457–1464
1459
acid in CH2Cl2 at room temperature for 24 h and then treating the obtained oxide with dimethylcarbamoyl
chloride and trimethylsilylcyanide in CH2Cl2 at room temperature for 6 days.8
Scheme 2.
With the ligands 5c–f in hand, their ability to provide asymmetric induction in the palladium-
catalyzed alkylation of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate was examined. Allylic
substitutions were carried out at room temperature 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 potassium acetate in a methylene chloride solution.9
The results obtained under control of the new ligands are summarized in Table 1 from which the
following conclusions can be made: (i) a dramatic effect on the catalytic activity is observed by the
presence in the pyridine ring of the pyridyloxazolines of electron-donating (5c, 5e) or withdrawing
Table 1
Allylic alkylation of 1,3-diphenylprop-2-enyl acetate with dimethyl malonatea

1460
G. Chelucci et al. / Tetrahedron: Asymmetry 10 (1999) 1457–1464
(5d, 5f) groups. The electron-donating group (5c, 5e) increases the reaction rate with respect to the
4-unsubstituted oxazolinylpyridine 5a (entry 2 versus 1 and entry 5 versus 4) whereas the electron-
withdrawing substituent decreases it drastically (entry 3 versus 1 and entry 6 versus 4); (ii) in contrast, the
enantioselectivity of the substitution reaction appears to be scarcely affected by the electronic properties
of the ligand. Thus, the ligands containing both electron-donating or withdrawing groups give a product
possessing a similar enantiomeric excess and the same sense of chirality from that obtained from the
related 4-unsubstituted ligands (entries 2, 3 versus 1 and entries 5, 6 versus 4).
These results indicate that the catalytic activity of the ligand is strongly dependent on its electronic
properties, whereas its stereodifferentiating ability appears to be chiefly determined by its steric pro-
perties, although a favorable affect (albeit modest) on the enantioselectivity is observed with the ligand
5f bearing an electron-donating substituent on the pyridine and a crowded group on the oxazoline ring
(Table 1: entry 6 versus 4).
Starting from these observations, it appeared interesting to synthesize an oxazolinylpyridine in which
steric and electronic factors work together so as to optimize the asymmetric reaction. To this end we
decided to synthesize oxazolinylpyridine 9 (Scheme 3) using both a methoxy and a methyl group on the 4-
and 6-positions of the pyridine ring and a tert-butyl substituent on the oxazoline, since good results have
been obtained in the enantioselective palladium-catalyzed allylic substitution of 1,3-diphenylprop-2-enyl
acetate with dimethyl malonate using as a ligand the related 2-[4,5-dihydro-4-(1,1-dimethylethyl)oxazol-
2-yl]-6-methylpyridine 10 (91% ee, Table 1). In other words, we decided to prepare 9 with the aim of
combining the favorable electronic effect of the methoxy group and the steric effect of the methyl and
tert-butyl groups.
Scheme 3.
The oxazolinylpyridine 9 was prepared from the pyridine N-oxide 7 which was accessible following
the literature procedure10 (Scheme 3). Treatment of 7 with dimethylcarbamoyl chloride and trimethyl-
silylcyanide in CH2Cl2 at room temperature for 6 days afforded cyanoheterocycle 8 in very good yield
(92%).8 Finally, oxazolinylpyridine 9 was obtained by heating a chlorobenzene solution of 8 under reflux
with tert-leucinol in the presence of a catalytic amount of zinc chloride7 (72% yield).
Having prepared ligand 9, we studied its properties as a catalyst under the usual conditions. The data,
reported in Table 1, show that this ligand gives, with respect to the unsubstituted ligand 10, a slightly
better enantioselectivity but at a slightly worse reaction rate.
The results obtained can be tentatively explained as follows. With oxazolinylpyridines the two main
reactive diastereomeric π-allyl palladium complexes F and G [depicted in Scheme 4 for ligands with
(S)-configuration] interconvert through a π–σ–π mechanism and they are present at the equilibrium in
a different ratio. This ratio is determined by both the substituents on the 6-position of the pyridine and
on the 4-position of the oxazoline. In the absence of a substituent on the 6-position of the pyridine (i.e.,
with ligand 5) diastereomer F should be slightly more stable than G because of the steric repulsion in

G. Chelucci et al. / Tetrahedron: Asymmetry 10 (1999) 1457–1464
1461
this diastereomer between the phenyl group of the π-allyl moiety and the substituent on the oxazoline
ring, while the percentage of F would increase with the ligand 9 which has a bulkier substituent
than hydrogen on the 6-position of the pyridine ring. The stereochemical outcome suggests that the
nucleophile predominantly attacks the allylic terminus trans to the oxazoline nitrogen in the diastereomer
F (a in F) or cis in G (b in G). An electron-donating group makes the pyridine nitrogen a better σ-donor
than that of the oxazoline, whereas a withdrawing substituent makes it a worse σ-donor and, therefore,
it should increase or decrease the electronic density on the metal. In both cases, the two termini of the
allylic unit would respond in different ways to the electronic effect created on the metal by such a ligand
since the electronic properties of the ligand are predominantly relayed in a trans manner across the
complex. This electronic distortion upon the allylic moiety created by ligands with an electron-donating
group (5d, 5f) increases the reaction rate by making one of the two allylic termini of both diastereomers
F and G more susceptible to nucleophilic attack, but the absence of a preferred reactive complex, because
none of these diastereomers is particularly favored at the equilibrium, causes only a little change in the
enantioselection.11 On these grounds, a reduction of the catalytic activity should be expected with ligands
bearing a withdrawing group but not as dramatic as that observed in this case. The electronic control of
the reaction by the substituent could be otherwise rationalized considering the catalytic cycle of the
reaction caused by the oxidative addition of the allylic substrate to the palladium(0) catalyst (Scheme 1).
The rate of this step is dependent on the nature of the ligand and, in general, increases with increasing
basicity (ability to donate electrons to the metal) of the ligand which increases the electronic density on
the palladium and so its nucleophilic ability. These considerations are consistent with the observation
that electron donating groups increase the reaction rate, whereas electron withdrawing groups decrease
it drastically.
Scheme 4.
Neither of these mechanistic interpretations rationalize the unexpected decrease of the reaction rate
obtained with ligand 9. Clearly, in this case the catalytic activity is strongly dependent on the steric
properties of the ligand. In fact, the rate of the oxidative addition step can be decreased not only by
reducing the electronic density on the palladium but also by improving the steric requirement of the
ligand. Thus, the electronic effect of the methoxy group appears relevant for the slightly crowed ligands
5d, 5f but it becomes unimportant in the case of the more sterically demanding ligand 9. However, the
observed improved enantioselectivity obtained with the ligand 9 confirms the favorable electronic effect
on the stereoselectivity of the methoxy group which favors the nucleophilic attack on the C1 carbon of
the preferred diastereomer F, as previously observed with ligand 5f.
3. Conclusions
The catalytic activity in the palladium-catalyzed allylic substitution of 1,3-diphenylprop-2-enyl ace-
tate, with dimethyl malonate using chiral oxazolinylpyridines bearing electron-donating and withdrawing

1462
G. Chelucci et al. / Tetrahedron: Asymmetry 10 (1999) 1457–1464
groups in the pyridine ring, was found to be highly dependent upon the electronic properties of the
ligands. As previously mentioned, the electron-donating group increases the reaction rate, whereas the
electron-withdrawing group decreases it drastically. In contrast, the enantioselectivity of the substitution
reaction was scarcely affected by the electronic properties of the ligand. With the aim of obtaining a
ligand in which steric and electronic factors work together so as to optimize the asymmetric reaction, we
prepared oxazolinylpyridine 9 which gave a slightly better enantioselectivity (93% ee) with respect to the
unsubstituted ligand 10. The catalytic activity and stereochemical results has been tentatively rationalized
on the basis of considerations on the transition states and related rates.
4. Experimental
4.1. General methods
Boiling points are uncorrected. Melting points were determined on a Buchi 510 capillary apparatus and
are uncorrected. The 1H NMR (300 MHz) spectra were obtained with a Varian VXR-300 spectrometer.
Optical rotations were measured with a Perkin–Elmer 241 polarimeter in a 1 dm tube. Elemental
analyses were performed on a Perkin–Elmer 240 B analyzer. 4-Chloro-2-cyanoypyridine 3,12 2-cyano-
4-methoxypyridine13 4, 4-methoxy-2-methylpyridine-N-oxide 710 were prepared following a literature
procedure.
4.2. 2-Cyano-3-methoxy-6-methylpyridine 8
Dimethylcarbamoyl chloride (1.44 g, 13.5 mmol) was added dropwise to a solution of N-oxide of 7
(1.87 g, 13.5 mmol) and trimethylsilylcyanide (1.59 g, 14.8 mmol) in CH2Cl2 (100 ml). The solution was
stirred at room temperature for 5 days, then 10% K2CO3 was added and stirring continued for 15 min.
The organic phase was separated and dried (Na2SO4), and the solvent was evaporated. The residue was
taken up with ethyl ether and the solid formed was filtered to give 8: 1.84 g (92% yield); mp 105–107°C;
1H NMR (CDCl3) δ: 7.09 (d, 1H, J=2.4 Hz), 6.87 (d, 1H, J=2.4 Hz), 3.90 (s, 3H), 2.55 (s, 3H). Anal.
calcd for C8H8N2O: C, 64.85; H, 5.44; N, 18.91. Found: C, 64.66; H, 5.41; N, 18.76.
4.3. General procedure for the preparation of oxazolinylpyridines
In a 25 ml two-necked flask zinc chloride (14 mg, 0.10 mmol) was melted under high vacuum and
cooled under argon. After cooling to room temperature, chlorobenzene (12 ml) was added followed by
the nitrile (2 mmol) and the amino alcohol (3.0 mmol). The resulting mixture was heated under reflux for
the proper time (vide infra) and then the solvent was evaporated under reduced pressure. The residue was
dissolved in CH2Cl2 (6 ml) and the resulting solution was washed with water (3×4 ml). The aqueous
solution was extracted with CH2Cl2 (6 ml), the combined organic phases were dried over anhydrous
Na2SO4, and the solvent evaporated. The residue was purified by chromatography on a silica gel column
with the indicated eluent.
4.3.1. (S)-4-Chloro-2-[4,5-dihydro-4-(1-methylethyl)oxazol-2-yl]pyridine 5c
Reaction time: 48 h; chromatographic eluent: benzene:acetone, 8:2; 0.217 g (48%); oil; [α]25 −61.4
D
(c 1.2, CHCl3); 1H NMR (CDCl3) δ: 8.60 (d, 1H, J=5.2 Hz), 8.08 (d, 1H, J=2.0 Hz), 7.41 (dd, 1H, J=5.2,
2.0 Hz), 4.51 (t, 1H, J=8.5 Hz), 4.26–4.12 (m, 2H), 1.91 (m, 1H), 1.07 (d, 3H, J=6.9 Hz), 0.95 (d, 3H,

G. Chelucci et al. / Tetrahedron: Asymmetry 10 (1999) 1457–1464
1463
J=6.9 Hz). Anal. calcd for C11H13ClN2O: C, 58.80; H, 5.83; N, 12.47; Cl, 15.78. Found: C, 58.65; H,
5.84; N, 12.43; Cl, 15.60.
4.3.2. (S)-2-[4,5-Dihydro-4-(1-methylethyl)oxazol-2-yl]-4-methoxypyridine 5d
Reaction time: 48 h; chromatographic eluent (Al2O3): benzene:acetone, 1:1; 0.130 g (30%); oil; [α]25
D
−64.5 (c 1.0, CHCl3); 1H NMR (CDCl3) δ: 8.49 (d, 1H, J=5.7 Hz), 7.60 (d, 1H, J=2.5 Hz), 6.89 (dd, 1H,
J=5.7, 2.5 Hz), 4.50 (t, 1H, J=8.5 Hz), 4.25–4.11 (m, 2H), 3.89 (s, 3H, CH3O), 1.91 (m, 1H), 1.07 (d,
3H, J=6.9 Hz), 0.95 (d, 3H, J=6.9 Hz). Anal. calcd for C12H16N2O2: C, 65.43; H, 7.32; N, 12.72. Found:
C, 65.35; H, 7.18; N, 12.58.
4.3.3. (S)-4-Chloro-2-(4,5-dihydro-4-phenyloxazol-2-yl)pyridine 5e
Reaction time: 48 h; chromatographic eluent: benzene:acetone, 8:2; 0.29 g (57%); oil; [α]25 +4.0
D
1
(c 1.1, CHCl3); H NMR (CDCl3) δ: 8.61 (d, 1H, J=5.1 Hz), 8.20 (d, 1H, J=1.8 Hz), 7.42–7.23 (m,
6H), 5.47 (dd, 1H, J=9.6, 9.0 Hz), 4.90 (dd, 1H, J=9.6, 9.0 Hz), 4.42 (t, 1H, J=8.7 Hz). Anal. calcd for
C14H11ClN2O: C, 65.00; H, 4.29; N, 10.83; Cl, 13.70. Found: C, 64.88; H, 4.53; N, 10.70; Cl, 13.54.
4.3.4. (R)-2-(4,5-Dihydro-4-phenyloxazol-2-yl)-4-methoxypyridine 5f
Reaction time: 48 h; chromatographic eluent: benzene:acetone, 8:2; 0.30 g (61%); oil; [α]25 +83.9 (c
D
1
1.2, CHCl3); H NMR (CDCl3) δ: 8.51 (d, 1H, J=5.7 Hz), 7.68 (d, 1H, J=2.4 Hz), 7.39–7.24 (m, 5H),
6.91 (dd, 1H, J=5.7, 2.4 Hz), 5.48 (dd, 1H, J=9.6, 9.0 Hz), 4.91 (dd, 1H, J=9.6, 9.0 Hz), 4.43 (t, 1H, J=8.7
Hz), 3.85 (s, 3H, CH3O). Anal. calcd for C15H14N2O2: C, 70.85; H, 5.55; N, 11.02. Found: C, 70.93; H,
5.68; N, 10.77.
4.3.5. (S)-2-[4,5-Dihydro-4-(1,1-dimethylethyl)oxazol-2-yl]-4-methoxy-6-methylpyridine 9
Reaction time: 24 h; chromatographic eluent: benzene:acetone, 8:2; 0.57 g (72%); mp 97–98°C; [α]25
D
−77.1 (c 1.1, CHCl3); 1H NMR (CDCl3) δ: 7.50 (d, 1H, J=2.4 Hz), 6.76 (d, 1H, J=2.4 Hz), 4.44 (dd, 1H,
J=10.2, 8.7 Hz), 4.31 (t, 1H, J=8.1 Hz), 4.09 (dd, 1H, J=10.2, 8.1 Hz), 3.88 (s, 3H, CH3O), 2.58 (s, 3H,
CH3), 0.97 (s, 9H, t-bu). Anal. calcd for C14H20N2O2: C, 67.72; H, 8.12; N, 11.28. Found: C, 67.55; H,
8.35; N, 11.31.
4.4. Allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate: general procedure
A solution of ligand (0.04 mmol, 10 mol%) and [{Pd(η3-C3H5)Cl}2] (4 mg, 2.5 mol%) in dry CH2Cl2
(2 ml) was stirred at room temperature for 15 min. This solution was treated successively with a solution
of rac-(E)-1,3-diphenyl-2-propenyl acetate (0.4 mmol) in CH2Cl2 (1 ml), dimethyl malonate (1.2 mmol),
N,O-bis(trimethylsilyl)acetamide (1.2 mmol) and anhydrous potassium acetate (3.5 mol%). The reaction
mixture was stirred for the appropriate time (see Table 1) until conversion was complete as shown by TLC
analysis (light petroleum:ether, 3:1). The reaction mixture was diluted with ether (25 ml) and washed with
ice-cold saturated aqueous ammonium chloride. The organic phase was dried (Na2SO4) and concentrated
under reduced pressure. The residue was purified by flash chromatography (light petroleum:ether, 3:1) to
afford dimethyl 1,3-diphenylprop-2-enylmalonate. The enantiomeric excess was determined from the 1H
NMR spectrum in the presence of enantiomerically pure shift reagent Eu(hfc)3; splitting of the signals
for one of the two methoxy groups was observed.

1464
G. Chelucci et al. / Tetrahedron: Asymmetry 10 (1999) 1457–1464
Acknowledgements
Financial support by M.U.R.S.T. and by Regione Autonoma Sardegna is gratefully acknowledged.
References
1. For reviews: Trost, M. B.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395. Hayashi, T. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH: Weinheim, 1993. Frost, C. G.; Howarth, J.; Williams, J. M. J. Tetrahedron: Asymmetry 1992, 3, 1089.
For more recent references on palladium-catalyzed allylic alkylation reactions, see: Koning, B.; Meetsma, A.; Kellogg, R.
M. J. Org. Chem. 1998, 63, 1604.
2. Ward, T. R. Organometallics 1996, 15, 2836. Steinhagen, H.; Reggelin, M.; Helmchen, G. Angew. Chem., Int. Ed. Engl.
1997, 2108.
3. Prétôt, R.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1998, 323.
4. Chelucci, G.; Medici, S.; Saba, A. Tetrahedron: Asymmetry 1999, 10, 543. Chelucci, G.; Medici, S.; Saba, A. Tetrahedron:
Asymmetry 1997, 8, 3183. For a related study see: Nordström, K.; Macedo, E.; Moberg, C. Tetrahedron: Asymmetry 1998,
9, 3437.
5. Chelucci, G. Tetrahedron: Asymmetry 1997, 8, 2667. For other applications of oxazolinylpyridines for palladium-catalyzed
allylic substitutions see: Nordström, K.; Macedo, E.; Moberg, C. J. Org. Chem. 1997, 62, 1604.
6. For analogue strategies see: Park, S.-B.; Murata, K.; Matsumoto, H.; Nishiyama, H. Tetrahedron: Asymmetry 1995, 6,
2487 and references therein.
7. Bolm, C.; Veickhardt, K.; Zehnder, M.; Ranff, T. Chem. Ber. 1991, 124, 1173.
8. Fife, W. K. J. Org. Chem. 1983, 48, 1375
9. Trost, B. M.; Murphy, D. J. Organometallics 1985, 4, 1143.
10. Deady, L. W.; Shanks, R. A.; Campbell, A. D.; Chooi, S. Y. Aust. J. Chem. 1971, 24, 385
11. Blöchl, P. E.; Togni, A. Organometallics, 1996, 15, 4125.
12. Tani, H. Yakugaku Zasshi 1960, 80, 1418. C.A. 55, 9477
13. Shuman, R. T.; Ornstein, P. L.; Paschal, J. W.; Gesellchen, P. D. J. Org. Chem. 1990, 55, 738