Chiral pyridylmethyl- and quinolinyl-oxazolines as ligands for enantioselective palladium-catalyzed allylic alkylation

Article abstract of DOI:10.1016/S0957-4166(99)00114-7

Chiral pyridylmethyl- and quinolinyl-oxazolines were prepared and assessed in the enantioselective palladium-catalyzed allylic substitution of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate. Enantioselectivities up to 77% were obtained.

Full text of DOI:10.1016/S0957-4166(99)00114-7

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1393–1400
Chiral pyridylmethyl- and quinolinyl-oxazolines as ligands for
enantioselective palladium-catalyzed allylic alkylation
Giorgio Chelucci,∗ Serafino Gladiali and Antonio Saba
Dipartimento di Chimica, Università di Sassari, via Vienna 2, I-07100 Sassari, Italy
Received 10 March 1999; accepted 25 March 1999
Abstract
Chiral pyridylmethyl- and quinolinyl-oxazolines were prepared and assessed in the enantioselective palladium-
catalyzed allylic substitution of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate. Enantioselectivities up to
77% were obtained. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Palladium complexes using a variety of P–P-, P–N- and N–N-based ligands, with C1 as well as C2
symmetry, have been proven to induce impressive levels of enantioselectivity in the catalyzed asymmetric
C–C bond forming reactions with allylic compounds.1 Recently, we and others have introduced the use
of chiral oxazolinylpyridines as ligands for enantioselective palladium-catalyzed allylic substitutions,
obtaining nearly absolute enantiomeric excesses in the alkylation of 1,3-diphenylprop-2-enyl acetate with
dimethyl malonate.2 More recently, by using this process, we have prepared and assessed a number of
chiral oxazolinylpyridines 1 (Scheme 1) having different substituents (alkyl, aryl, electron-donating and
withdrawing groups) on the pyridine and oxazoline rings and we have disclosed their cross effects on the
catalytic activity and stereoselectivity of the process (steric control and electronic control).3
Scheme 1.
∗
Corresponding author.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00114-7

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While pursuing our work in this field (in the search of a ring-size control in this reaction) we have
been attracted by the possibility of modifying the structure of the pyridyloxazoline ligands by changing
the chelate ring size of the Pd complex. In fact, the significance of this parameter on the design of
chiral ligands for asymmetric catalysis has been pointed out previously.4 Since the pyridyloxazolines
form a five-membered chelate ring, we became interested in obtaining ligands bearing both a pyridine
and an oxazoline moiety which, by coordination with the metal, form a six-membered chelate ring.
Expansion to a six-membered chelate ring of the pyridyloxazoline ligands can be obtained in the most
simple approach by interposing a one-carbon spacer between the two heterocyclic units. Insertion of a
methylene unit would result in the conformationally mobile pyridylmethyloxazolines 2,5 while ligands
of increased stiffness6 could be obtained appending the oxazoline substituent onto the quinolyl scaffold,
as in the case of derivative 3.7
We report here on the synthesis of pyridylmethyl- and quinolinyl-oxazolines 2 and 3 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
2.1. Synthesis of ligands
Pyridylmethyloxazolines 2 were easily prepared by heating a chlorobenzene solution of 2-
cyanomethylpyridine 4 under reflux with the appropriate aminoalcohol in the presence of a catalytic
amount of zinc chloride8 (42–57% yield; Scheme 2). These ligands provided a disappointingly low
asymmetric induction in the palladium-catalyzed alkylation of 1,3-diphenylprop-2-enyl acetate (Table 1).
Scheme 2.
We then devoted our attention to the preparation of the related quinolinyl-oxazoline 3. Since our
initial attempts to achieve direct condensation of 8-cyanoquinoline with (S)-valinol failed, a conventional
protocol involving the sequence amide–mesylate–oxazoline was evaluated9 (Scheme 3). Heating 8-
quinolinecarboxylic acid methyl ester (5) under reflux with the appropriate aminoalcohol in the presence
of a catalytic amount of potassium cyanide10 gave the corresponding amides 6a–c in an almost quanti-
tative yield. The reaction of 6 with MeSO2Cl in Et3N/CH2Cl2 did not give the relevant 7 but afforded a
mixture of the oxazolines 3 and chlorides 8 (derived from nucleophilic attack of the chloride ion on the
intermediate 7) in about a 1:1 ratio. Since these chlorides were successfully cyclized into 3 by treatment
with 5% KOH in refluxing methanol, in further preparations the crude mixtures obtained by cyclization
of amides 6 were treated with KOH to provide the desired ligands 3a–c in good overall yield (50–74%).
Both ligands 2 and 3 are fairly unstable compounds and upon standing at room temperature for some
weeks they undergo ring opening to the corresponding amides.

G. Chelucci et al. / Tetrahedron: Asymmetry 10 (1999) 1393–1400
1395
Table 1
Allylic alkylation of 1,3-diphenylprop-2-enyl acetate with dimethyl malonatea
Scheme 3.

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2.2. Palladium-catalyzed allylic alkylation
Allylic substitutions were carried out employing Trost’s procedure which demands the use of [Pd(η3-
C3H5)Cl]2 as procatalyst and a mixture of dimethyl malonate, N,O-bis(trimethylsilyl)acetamide (BSA)
and potassium acetate in methylene chloride at room temperature.11
The results obtained in a set of experiments with the new ligands are summarized in Table 1.
Contrasting results were obtained with pyridylmethyloxazoline ligands 2a and 2b. Whereas the catalyst
originating from 2a led to total conversion of the starting material 9 in less than 4 h, affording the 1,3-
diphenylprop-2-enylmalonate 10 in high yield, the palladium complex obtained from ligand 2b required,
for the complete conversion of 9, a reasonably long reaction time (75 h). With both ligands 2a and
2b, catalytic activity and enantioselectivity were lower than those obtained with the related 2-[4,5-
dihydro-4-(1-methylethyl)oxazol-2-yl]pyridine 1a and 2-(4,5-dihydro-4-phenyloxazol-2-yl)pyridine 1b
(entries 2 versus 1 and 4 versus 3). These results appear to indicate that the five-membered chelate ring
palladium–pyridyloxazoline catalysts are more enantioselective than the corresponding six-membered
counterparts despite the fact that in the latter case the substituent at the stereocentre is closer to the
allylic termini and is expected to exert a larger influence on the stereoselectivity of the reaction. We may
speculate whether this result is related to the increased degree of conformational mobility attained by the
ligand when the pyridine and the oxazoline rings are separated by the methylene spacer. This hypothesis
seems corroborated by the results observed with the ligands 3. The Pd catalysts formed by both 3a and 3b
were more active and enantioselective than the ones obtained from the corresponding ligands 2 (entries
6 versus 2 and 7 versus 4). Interestingly, they were slightly better even than the relevant five-membered
counterparts 1 (entries 5 versus 1 and 6 versus 3). The best enantioselectivity (77% ee) was obtained with
ligand 3c bearing the tert-butyl group on the oxazoline moiety.
The different behaviours of these ligands can be explained by considering the related π-allyl palladium
complexes. 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 which interconvert through a π–σ–π mechanism and which
are present in the equilibrium in a different ratio (for instance 11 and 12 for ligands with the (S)-
configuration: Scheme 4). Since the prevailing configuration obtained in the substitution product 10 is
the one expected from the configuration of the oxazoline stereocentre, it is reasonable to assume that the
reactive transition states are the same as those previously observed using pyridyloxazolines 1. We may
then draw the conclusion that also in this case the nucleophile predominantly attacks the allylic terminus
trans to the oxazoline nitrogen in the more stable diastereomer 11.2,3
Scheme 4.

G. Chelucci et al. / Tetrahedron: Asymmetry 10 (1999) 1393–1400
1397
3. Conclusions
Since it has usually been observed that the prevailing reaction product comes from a nucleophilic attack
to the allylic terminus of the most abundant complex,12 the ability of the ligand to stabilize one of the two
diastereomeric complexes is a crucial point in determining the stereochemical outcome. Both ligands 1
and 3 provide rigid structures where the chelate rings, albeit of different sizes, are substantially planar.
Therefore, in both cases stabilization of the diastereomeric transition state 11 should rely on similar
arguments and the enantioselection is expected to improve as the chirogenic element of the ligand gets
closer to the metal centre, as occurs in the case of the six-membered ring. The pyridylmethyloxazolines
2 coordinate to the metal in the same way as the ligands 3, but the chelate ring is no more rigid in this
case and can adopt different conformations. This should result in an increased number of diastereomeric
transition states of different reactivities which can be responsible for the low enantiomeric excesses
observed.
We are currently addressing our efforts to modify the structure of the pyridylmethyl- and quinolinyl-
oxazolines in order to optimize their use in this and other asymmetric processes.
4. Experimental
4.1. General methods
Boiling points are uncorrected. Melting points were determined on a Büchi 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 analyser. 2-Cyanomethylpyridine 4 was a commercial product
(Aldrich A.G.) and 8-quinolinecarboxilic acid methyl ester 513 was prepared following the literature
procedure.
4.2. General procedure for the preparation of oxazolinylmethylpyridines 2
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 nitrile (2 mmol) and the aminoalcohol (3.0 mmol). The resulting mixture was heated under reflux
for the appropriate 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 was evaporated. The residue was purified by chromatography on a
silica gel column (benzene:acetone, 8:2).
4.2.1. (S)-2-{[4,5-Dihydro-4-(1-methylethyl)oxazol-2-yl]methyl}pyridine 2a
25
Reaction time: 48 h; 0.230 g (57%); oil; [α]D −62.1 (c 1.2, CHCl3); 1H NMR (CDCl3) δ: 8.53 (d,
1H, J=4.5 Hz), 7.62 (dt, 1H, J=7.8, 1.8 Hz), 7.32 (d, 1H, J=7.8 Hz), 7.14 (dd, 1H, J=5.4, 6.9 Hz), 4.23
(m, 1H), 3.91 (m, 2H), 3.84 (s, 2H), 1.75 (m, 1H), 0.95 (d, 3H, J=6.9 Hz), 0.87 (d, 3H, J=6.9 Hz). Anal.
calcd for C12H16N2O: C, 70.54; H, 7.90; N, 13.72. Found: C, 70.22; H, 7.84; N, 13.43.

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4.2.2. (R)-2-[(4,5-Dihydro-4-phenyloxazol-2-yl)methyl]pyridine 2b
Reaction time: 96 h; 0.200 g (42%); 72–74°C; [α]D25 +10.3 (c 1.0, CHCl3); 1H NMR (CDCl3) δ: 8.58
(d, 1H, J=4.2 Hz), 7.62 (dt, 1H, J=7.5, 1.5 Hz), 7.40–7.17 (m, 7H), 5.21 (t, 1H, J=9.3 Hz), 4.63 (dd, 1H,
J=8.4, 9.9 Hz), 4.11 (t, 1H, J=8.7 Hz), 3.95 (s, 2H). Anal. calcd for C15H14N2O: C, 75.60; H, 5.93; N,
11.76. Found: C, 75.55; H, 5.98; N, 11.58.
4.3. General procedure for the preparation of 8-quinolinecarboxamides 6
A mixture of 8-quinolinecarboxylic acid methyl ester 5 (1 g, 5 mmol), the aminoalcohol (6.5 mmol)
and KCN (65 mg, 1 mmol) in toluene (15 ml) was heated under reflux for 24 h. The solvent was
evaporated under reduced pressure and the residue was purified by chromatography on a silica gel column
with the indicated eluent if not otherwise stated.
4.3.1. (S)-N-[2-Hydroxy-1-(1-methylethyl)ethyl]-8-quinolinecarboxamides 6a
Chromatographic eluent: benzene:acetone, 1:1; 1.23 g (95%); oil; 1H NMR (CDCl3) δ: 11.47 (d, 1H,
J=7.2 Hz), 8.74 (dd, 1H, J=4.2, 1.6 Hz), 8.70 (dd, 1H, J=7.4, 1.6 Hz), 8.08 (dd, 1H, J=8.2, 1.6 Hz), 7.75
(dd, 1H, J=8.2, 1.6 Hz), 7.43 (t, 1H, J=7.8 Hz), 7.30 (dd, 1H, J=8.4, 5.0 Hz), 4.15 (broad, 1H), 4.05
(m, 1H), 3.75 (m, 2H), 2.05 (m, 1H), 0.99 (d, 3H, J=3.8 Hz), 0.95 (d, 3H, J=3.8 Hz). Anal. calcd for
C15H18N2O2: C, 69.73; H, 7.03; N, 10.84. Found: C, 69.88; H, 7.12; N, 10.70.
4.3.2. (R)-N-[2-Hydroxy-1-phenylethyl]-8-quinolinecarboxamides 6b
In this case the residue was taken up with ethyl ether to give a white solid: 1.34 g (96%); mp
1
155–156°C. H NMR (CDCl3) δ: 12.12 (d, 1H, J=5.9 Hz), 8.89 (d, 1H, J=4.1 Hz), 8.82 (d, 1H, J=7.3
Hz), 8.30 (dd, 1H, J=8.3, 1.2 Hz), 7.98 (d, 1H, J=8.1 Hz), 7.46 (t, 1H, J=7.7 Hz), 7.55–7.12 (m, 6H),
5.49 (m, 1H), 4.04 (m, 2H), 3.58 (broad, 1H). Anal. calcd for C18H16N2O2: C, 73.94; H, 5.53; N, 9.58.
Found: C, 73.93; H, 5.68; N, 9.77.
4.3.3. (S)-N-[2-Hydroxy-1-(1,1-dimethylethyl)ethyl]-8-quinolinecarboxamides 6c
1
Chromatographic eluent: benzene:acetone, 8:2; 1.17 g (87%); mp 138–140°C; H NMR (CDCl3) δ:
11.70 (d, 1H, J=5.5 Hz), 8.93 (dd, 1H, J=4.3, 1.8 Hz), 8.86 (dd, 1H, J=7.4, 1.6 Hz), 8.33 (dd, 1H, J=8.3,
1.8 Hz), 7.98 (dd, 1H, J=8.1, 1.6 Hz), 7.70 (t, 1H, J=7.8 Hz), 7.52 (dd, 1H, J=8.3, 4.3 Hz), 4.15 (dt, 1H,
J=8.4, 1.8 Hz), 4.06 (dd, 1H, J=8.4, 1.4 Hz), 3.73 (m, 2H), 1.14 (s, 9H). Anal. calcd for C16H20N2O2: C,
70.55; H, 7.41; N, 10.29. Found: C, 70.63; H, 7.48; N, 10.27.
4.4. General procedure for the preparation of oxazolinylquinolines 3
Methanesulfonyl chloride (0.38 ml, 6.25 mmol) was added to a cold (0°C) solution of quinolinecarbox-
amides (5 mmol) and Et3N (1.39 ml, 10 mmol) in CH2Cl2 (20 ml). The reaction mixture was allowed to
warm to room temperature and stirring was continued overnight. The reaction mixture was then poured
into a saturated aqueous ammonium chloride solution, the organic layer was separated and the aqueous
layer was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4) and concentrated
under reduced pressure. The residue was taken up with a 5% KOH methanolic solution (20 ml) and the
resulting solution was heated under reflux for 3 h. The solvent was evaporated and the residue was poured
into water and extracted with CH2Cl2. The organic phase was dried (Na2SO4) and concentrated under
reduced pressure. The residue was purified by chromatography on a silica gel column with the indicated
eluent.

G. Chelucci et al. / Tetrahedron: Asymmetry 10 (1999) 1393–1400
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1
4.4.1. (S)-8-[4,5-Dihydro-4-(1-methylethyl)oxazol-2-yl]quinoline 3a
25
Chromatographic eluent: benzene:acetone, 1:1; 0.94 g (78%); oil; [α]D −57.6 (c 1.0, EtOH). H
NMR (CDCl3) δ: 9.05 (d, 1H, J=5.9 Hz), 8.17 (dd, 1H, J=8.3, 1.7 Hz), 8.12 (dd, 1H, J=7.3, 1.4 Hz), 7.90
(dd, 1H, J=8.4, 1.4 Hz), 7.56 (dd, 1H, J=8.1, 1.4 Hz), 7.43 (dd, 1H, J=8.1, 4.2 Hz), 4.56 (m, 1H), 4.28
(m, 2H), 2.02 (m, 1H), 1.12 (d, 3H, J=6.8 Hz), 1.03 (s, 3H, J=6.8 Hz). Anal. calcd for C15H16N2O: C,
74.97; H, 6.71; N, 11.66. Found: C, 74.63; H, 6.68; N, 11.67.
4.4.2. (R)-8-(4,5-Dihydro-4-phenyloxazol-2-yl)quinoline 3b
25
1
Chromatographic eluent: ethyl acetate; 0.81 g (62%); oil [α]D +38.9 (c 1.0, EtOH). H NMR
(CDCl3) δ: 9.09 (dd, 1H, J=4.2, 1.8 Hz), 8.24 (dd, 1H, J=6.9, 1.5 Hz), 8.19 (dd, 1H, J=8.4, 1.8 Hz),
7.95 (dd, 1H, J=8.4, 1.5 Hz), 7.59 (t, 1H, J=7.2 Hz), 7.20–7.55 (m, 6H), 5.57 (dd, 1H, J=10.2, 8.1 Hz),
4.97 (dd, 1H, J=10.2, 1.7 Hz), 4.45 (t, 1H, J=8.3 Hz). Anal. calcd for C18H14N2O: C, 78.81; H, 5.14; N,
10.21. Found: C, 78.73; H, 5.18; N, 10.22.
4.4.3. (S)-8-[4,5-Dihydro-4-(1,1-dimethylethyl)oxazol-2-yl]quinoline 3c
25
Chromatographic eluent: benzene:acetone, 1:1; 0.79 g (58%); mp 137–139°C; [α]D −73.5 (c 1.1,
EtOH). 1H NMR (CDCl3) δ: 9.03 (dd, 1H, J=4.2, 1.8 Hz), 8.16 (dd, 1H, J=8.3, 1.8 Hz), 8.08 (dd, 1H,
J=7.1, 1.5 Hz), 7.90 (dd, 1H, J=8.2, 1.5 Hz), 7.56 (dd, 1H, J=8.2, 7.2 Hz), 7.42 (dd, 1H, J=8.3, 4.2 Hz),
4.57 (dd, 1H, J=10.1, 8.6 Hz), 4.39 (t, 1H, J=8.0 Hz), 4.20 (dd, 1H, J=10.1, 8.0 Hz), 1.05 (d, 9H, J=3.4
Hz). Anal. calcd for C16H18N2O: C, 75.56; H, 7.13; N, 11.01. Found: C, 75.63; H, 7.15; N, 11.07.
4.5. 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.
Acknowledgements
Financial support by M.U.R.S.T. and by Regione Autonoma Sardegna is gratefully acknowledged.
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