Synthesis and application of new iminopyridine ligands in the enantioselective palladium-catalyzed allylic alkylation

Article abstract of DOI:10.1016/j.molcata.2014.01.006

A variety of iminopyridines were obtained by condensation of chiral amines with pyridine-2-carboxaldehyde and quinoline-8-carbaldehyde, or of aminoalkylpyridine derivatives with chiral ketones. These ligands were assessed in the enantioselective palladium

Full text of DOI:10.1016/j.molcata.2014.01.006

Journal of Molecular Catalysis A: Chemical 385 (2014) 73–77
Contents lists available at ScienceDirect
Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
Synthesis and application of new iminopyridine ligands in the
enantioselective palladium-catalyzed allylic alkylation
Maurizio Solinasa, Barbara Sechia, Giorgio Cheluccib,∗, Salvatore Baldinob,
José R. Pedroc, Gonzalo Blayc
a CNR, Istituto di Chimica Biomolecolare UOS Sassari, Traversa La Crucca 3, I-07100 Sassari, Italy
b Dipartimento di Agraria, Università di Sassari, Viale Italia 39, 07100 Sassari, Italy
c Departament de Química Orgànica, Facultat de Química, Universitat de València, C/Dr. Moliner 50, E-46100 Burjassot (València), Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A
variety of iminopyridines were obtained by condensation of chiral amines with pyridine-2-
carboxaldehyde and quinoline-8-carbaldehyde, or of aminoalkylpyridine derivatives with chiral
ketones. These ligands were assessed in the enantioselective palladium catalyzed allylic substitution
of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate affording the product dimethyl 1,3-
diphenylprop-2-enylmalonate in good yields and moderate enantioselectivities (up to 62% ee). Catalytic
activity and enantioselectivity were found to be highly dependent upon the steric properties of the
ligands. The best enantioselectivity (62% ee) was obtained by an iminopyridine based on a camphane
skeleton.
Received 17 December 2013
Received in revised form 2 January 2014
Accepted 3 January 2014
Available online 26 January 2014
Keywords:
Iminopyridine ligands
Enantioselective catalysis
Allylic substitution
Palladium catalysis
© 2014 Elsevier B.V. All rights reserved.
1. Introduction
with diethylzinc [11]. Lacour and co-workers reported that the
combination of unsymmetrical iminopyridine ligands L2 (Fig. 1)
Transition-metal-catalyzed asymmetric allylic substitutions [1],
particularly those employing palladium- [2], copper- [3], iridium-
[4] or molybdenum-complexes [5] have become some of the most
powerful tools for asymmetric C C and C heteroatom bond forma-
tion, finding wide application in the synthesis of valuable molecules
and complex natural products [6].
In the past few decades, a plethora of efficient chiral ligands
has been developed for this asymmetric process. Most of them are
mixed bidentate donor ligands with P–P or P–N chelating mode
[1–6], although several interesting examples of N,N-chelating lig-
ands such as diamines [7], pyridine-based ligands (2,2ꢀ-bipyridines,
1,10-phenanthrolines, pyridyl amines, pyridyl oxazolines, etc.) [8]
and oxazoline-containing ligands [9] have also proven their effi-
ciency.
and the ruthenium complex [CpRu(MeCN)3]PF6 afforded highly
regio- and enantioselective Carroll rearrangements, this being
the first example of Ru-catalyzed asymmetric C C bond-forming
allylic substitution [12]. Finally, the tridentate PNN ligands L3a–c
(Fig. 1) were compared by Zheng and co-workers in the palladium-
catalyzed allylic alkylation of 1,3-diphenylprop-2-enyl pivalate and
cyclohexenyl acetate with dimethyl malonate in the presence of
BSA-KOAc, but as a result, it was found that the ligand L3a with a
2-pyridine N-atom surprisingly showed no activity, thus indicating
that this type of ligand works well only in a P–N chelating fashion
[13].
We have recently reported the synthesis and applica-
tion in the copper(II)-catalyzed Henry reaction of iminopy-
ridine ligands obtained by condensation of chiral amines
with pyridine-2-carboxaldehyde L2 or (5S,7R)-6,6-dimethyl-2-
phenyl-5,7-methanoquinolin-8(5H)-one L4 [14], or by reaction of
aminoalkylpyridines with naturally occurring chiral ketones L5
[15]. Since, as mentioned-above, these type of chiral ligands have
been never applied in Pd-catalyzed allylic substitutions, in line
with our ongoing efforts to explore highly enantioselective reac-
tions using simple and cheap chiral catalytic systems [16], we
have investigated the potential of this type of chiral ligands in
asymmetric Pd-catalyzed allylic substitutions. Herein we report
the comparative results obtained in the Pd-catalyzed allylic alkyl-
ation of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate
Notwithstanding chiral N,N-ligands based on imino and pyri-
dine moieties have become
a large and important topic in
asymmetric synthesis, they have been barely applied in allylic
substitution reactions [10]. Hoveyda and co-workers developed
readily modular peptide-based iminopyridine ligands 1 (Fig. 1),
which led to an interesting level of regio- and enantioselectivity
in the Cu-catalyzed allylic substitution of cinnamyl phosphates
∗
Corresponding author. Tel.: +39 079 229539; fax: +39 079 229559.
E-mail address: chelucci@uniss.it (G. Chelucci).
1381-1169/$ – see front matter © 2014 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molcata.2014.01.006

74
M. Solinas et al. / Journal of Molecular Catalysis A: Chemical 385 (2014) 73–77
R1
R2
Z
R3
O
H
N
N
R2
N
X Y
N
NHBu
R1
N
PPh2
R3
N
O
Fe
R4
L1
L3a-c
L2
a: X = N, Y = Z = CH
b: Y = N, X = Z = CH
c: Z = N, X = Y = CH
R2
( )
n
R2
H
N
N
N
Ph
N
N
N
L6
R3
*R
*R
R1
L4
L5
Fig. 1. Ligands applied in allylic substitution reactions.
using the known iminopyridines of the type L2 and L5, and the new
iminopyridines L6 (Fig. 1). It should be noted that all the examined
ligands share the imino and pyridine moieties, but differ from their
chelating properties. In fact, both ligands L2 and L5 (n = 0) form
a five-membered chelate ring with palladium, but differ from the
orientation of the N C double bond, which is directed forward the
pyridine ring in ligands L2 and in the opposite side in ligands L5.
On the other hand, ligands L5 (n = 1) and L6 form a six-membered
chelate ring in a rather rigid structure.
2.2. General procedure for the synthesis of imines 5a–d,f,g
The proper amine (1.8 mmol) was added dropwise to a stirred
mixture of quinoline-8-carbaldehyde (0.28 g, 1.8 mmol) and anhy-
drous K2CO3 (0.5 g) in anhydrous diethyl ether (10 mL). The
resulting mixture was stirred at room temperature overnight and
then filtered. The organic phase was evaporated and the residue
was purified by flash chromatography eluting with petroleum
ether/EtOAc = 9:1.
2.2.1. (S,E)-N-(1-Phenylethyl)-1-(quinolin-8-yl)methanimine
(5a)
2. Experimental
Yield 82%; Pale yellow oil; [␣]D25 = −94.5 (c 0.5, CHCl3); 1H NMR
(400.1 MHz, CDCl3): ı = 9.78 (s, 1H, NCH), 8.96 (dd, J = 4.2, 1.8 Hz, 1H,
ArH), 8.52 (dd, J = 7.3, 1.5 Hz, 1H, ArH), 8.19 (dd, J = 8.3, 1.8 Hz, 1H,
ArH), 7.89 (dd, J = 8.1, 1.5 Hz, 1H, ArH), 7.60 (t, J = 7.6 Hz, 1H, ArH),
7.51 (d, J = 7.5 Hz, 2H, ArH), 7.44 (dd, J = 8.3, 4.2 Hz, 1H, ArH), 7.35 (t,
J = 7.5 Hz, 2H, ArH), 7.24 (t, J = 7.5 Hz, 1H, ArH), 4.77 (q, J = 6.6 Hz, 1H),
1.67 (d, J = 6.6 Hz, 3H, CH3); 13C NMR (100.6 MHz, CDCl3): ı = 157.3,
150.1, 146.8, 145.6, 136.4, 133.3, 128.5 (2C), 128.3, 127.9, 126.9 (2C),
126.8, 126.6, 126.4, 121.3, 70.4, 25.0; Anal. Calcd. for C18H16N2: C,
83.04; H, 6.19; N, 10.76. Found: C, 83.22; H, 6.20; N, 10.53.
2.1. General remarks
Ligand syntheses were carried out under nitrogen atmo-
sphere in oven-dried glassware with magnetic stirring, while
catalytic allylic alkylation reactions were performed without air
or moisture exclusion. Unless otherwise noted, all materials
were obtained from commercial suppliers and were used with-
out further purification. All solvents were HPLC grade. THF was
distilled from sodium-benzophenone ketyl and degassed thor-
oughly with dry nitrogen directly before use. Unless otherwise
noted, organic extracts were dried with Na2SO4, filtered through
a fritted glass funnel, and concentrated with a rotary evaporator
(20–30 mmHg). Flash chromatography was performed with sil-
ica gel (200–300 mesh) using the mobile phase indicated. Melting
points are collected using a BÜCHI B-540 and are uncorrected.
1H and 13C NMR spectra were recorded on a Varian Mercury (1H
400.1 MHz, 13C 100.6 MHz) with tetramethylsilane (TMS) as ref-
erence. Chemical shifts (ı) are reported in ppm and multiplicity
is indicated as follow: s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, bs = broad signal. Coupling constants (J) are indicated
in hertz. Ligands 2a–e [15], 2f [17], and 4a,c–g [14] were prepared
according to reported procedures.
2.2.2. (R,E)-N-(1-(Naphthalen-1-yl)ethyl)-1-(quinolin-8-
yl)methanimine
(5b)
Yield 84%; white solid mp 92–94 ◦C; [␣]D25 = −97.6 (c 1.1,
CHCl3); 1H NMR (400.1 MHz, CDCl3): ı = 9.89 (s, 1H, NCH), 8.96 (dd,
J = 4.2, 1.7 Hz, 1H, ArH), 8.59 (dd, J = 7.3, 1.5 Hz, 1H, ArH), 8.36 (d,
J = 8.4 Hz, 1H, ArH), 8.19 (dd, J = 8.3, 1.7 Hz, 1H, ArH), 7.94–7.87 (m,
3H, ArH), 7.76 (d, J = 8.2 Hz, 1H, ArH), 7.64 (t, J = 7.1 Hz, 1H, ArH),
7.57–7.43 (m, 4H, ArH), 5.58 (q, J = 6.6 Hz, 1H), 1.81 (d, J = 6.6 Hz, 3H,
CH3); 13C NMR (100.6 MHz, CDCl3): ı = 157.5, 149.9, 146.6, 141.6,
136.3, 133.9, 133.2, 130.6, 130.3, 128.8, 128.1, 127.7, 127.1, 126.5,
125.7, 125.6, 125.2, 123.9, 123.6, 121.2, 66.3, 24.8; Anal. Calcd. for
C22H18N2: C, 85.13; H, 5.85; N, 9.03. Found: C, 85.65; H, 5.90; N,
9.53.
2.1.1. (1R,4R)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-
ylidene)quinolin-8-amine
2.2.3.
(2f)
(R,E)-N-(1-Cyclohexylethyl)-1-(quinolin-8-yl)methanimine (5c)
Yield 81%; pale yellow oil; [␣]D25 = −38.0 (c 1.4, CHCl3); 1H NMR
(400.1 MHz, CDCl3): ı = 9.56 (s, 1H, NCH), 8.96 (dd, J = 4.2, 1.8 Hz,
1H, ArH), 8.44 (dd, J = 7.7, 1.5 Hz, 1H, ArH), 8.16 (dd, J = 8.3, 1.8 Hz,
1H, ArH), 7.86 (dd, J = 8.1, 1.5 Hz, 1H, ArH), 7.59 (t, J = 7.7 Hz, 1H,
ArH), 7.43 (dd, J = 8.3, 4.2 Hz, 1H, ArH), 3.27 (quin, J = 6.5 Hz, 1H, CH),
1.89–1.84 (m, 1H), 1.79–1.61 (m, 4H), 1.56–1.54 (m, 1H), 1.29 (d,
J = 6.5 Hz, 3H, CH3), overlapped with 1.34–1.12 (m, 3H), 0.98–0.94
(m, 2H); 13C NMR (100.6 MHz, CDCl3): ı = 156.5, 150.7, 146.8, 136.4,
133.6, 130.1, 128.4, 127.8, 126.7, 121.3, 72.3, 44.1, 30.2, 30.0, 26.8,
26.6, 26.5, 20.2; Anal. Calcd. for C18H22N2: C, 81.16; H, 8.32; N,
10.52. Found: C, 81.66; H, 8.55; N, 10.76.
This compound was prepared according to our procedure [17]:
mp 110–112 ◦C; [␣]D25 = −5.8 (c 1.0, CHCl3); 1H NMR (400.1 MHz,
CDCl3): ı = 8.10 (d, J = 4.4 Hz, 1H, ArH), 8.08 (d, J = 8.4 Hz, 1H, ArH),
7.50–7.41 (m, 2H, ArH), 7.32 (dd, J = 8.8, 4.4 Hz, 1H, ArH), 7.06 (d,
J = 6.8 Hz, 1H, ArH), 2.06 (dt, J = 17.2, 4.0 Hz, 1H), 1.92–1.74 (m, 4H),
1.50 (d, J = 17.2 Hz, 1H), 1.27–122 (m, 1H), overlapped with 1.25 (s,
3H, CH3), 1.04 (s, 3H, CH3), 1.00 (s, 3H, CH3). 13C NMR (100.6 MHz,
CDCl3): ı = 185.2, 148.8, 148.2, 139.3, 134.8, 128.0, 125.6, 121.3,
119.8, 116.9, 53.3, 46.6, 42.8, 36.1, 31.3, 26.4, 18.8, 18.2, 10.3. Anal.
Calcd. for C19H22N2: C, 81.97; H, 7.97; N, 10.06. Found: C, 82.33; H,
7.85; N, 10.01.

M. Solinas et al. / Journal of Molecular Catalysis A: Chemical 385 (2014) 73–77
75
2.2.4.
.
R1
R1
R2
BF3 OEt2
( )n
H2N
( )n
N
(R,E)-N-(3,3-Dimethylbutan-2-yl)-1-(quinolin-8-yl)methanimine
(5d)
+
O
N
N
toluene
n = 1, 2
R2
R3
R3
Yield 85%; pale yellow oil; [␣]D25 = −68.1 (c 1.1, CHCl3); 1H NMR
(400.1 MHz, CDCl3): ı = 9.59 (s, 1H, NCH), 8.97 (dd, J = 4.2, 1.8 Hz,
1H, ArH), 8.46 (dd, J = 7.7, 1.5 Hz, 1H, ArH), 8.17 (dd, J = 8.3, 1.8 Hz,
1H, ArH), 7.87 (dd, J = 7.7, 1.5 Hz, 1H, ArH), 7.60 (t, J = 7.7 Hz, 1H,
ArH), 7.43 (dd, J = 8.3, 4.2 Hz, 1H, ArH), 3.23 (quin, J = 6.6 Hz, 1H,
CH), 1.24 (d, J = 6.6 Hz, 3H, CH3), 0.98 (s, 9H); 13C NMR (100.6 MHz,
CDCl3): ı = 156.3, 150.1, 146.8, 136.5, 133.7, 129.9, 128.4, 127.8,
126.7, 121.3, 75.8, 34.6, 26.8 (3 C), 17.6; Anal. Calcd. for C16H20N2:
C, 79.96; H, 8.39; N, 11.66. Found: C, 79.46; H, 8.79; N, 10.86.
1a-c
2a-e
N
N
N
N
N
N
N
2a
2b
2c
1. BuLi, 2. MeI
N
2.2.5. (E)-1-(Quinolin-8-yl)-N-((2S,4R)-1,7,7-
trimethylbicyclo[2.2.1]heptan-2-yl)methanimine
(5f)
N
N
2d
2e
Yield 86%; white solid mp 126–129 ◦C; [␣]D25 = −5.1 (c 1.1,
CHCl3); 1H NMR (400.1 MHz, CDCl3): ı = 9.57 (s, 1H, NCH), 8.97 (dd,
J = 4.2, 1.8 Hz, 1H, ArH), 8.50 (dd, J = 7.3, 1.4 Hz, 1H, ArH), 8.19 (dd,
J = 8.3, 1.8 Hz, 1H, ArH), 7.89 (dd, J = 8.1, 1.4 Hz, 1H, ArH), 7.61 (t,
J = 7.7 Hz, 1H, ArH), 7.44 (dd, J = 8.3, 4.2 Hz, 1H, ArH), 3.72–3.68 (m,
1H, CH), 2.37–2.22 (m, 2H), 1.87–1.78 (m, 1H), 1.75 (t, J = 4.4 Hz,
1H), 1.50–1.44 (m, 1H), 1.40 (dd, J = 13.0, 3.9 Hz, 1H), 1.35–1.27 (m,
1H), 1.0 (s, 3H, CH3), 0.94 (s, 3H, CH3), 0.75 (s, 3H, CH3); 13C NMR
(100.6 MHz, CDCl3): ı = 157.0, 150.0, 146.8, 136.5, 133.8, 129.9,
128.4, 127.9, 126.7, 121.3, 76.0, 51.0, 48.6, 45.8, 37.6, 28.8, 28.6,
19.9, 19.0, 13.7; Anal. Calcd. for C20H24N2: C, 82.15; H, 8.27; N, 9.58.
Found: C, 82.51; H, 8.49; N, 9.80.
xylene, PTSA
+
N
N
N
dean-stark, reflux
NH2
O
2f
Scheme 1.
3. Results and discussion
3.1. Synthesis of the ligands
Iminopyridines 2a–d were easily obtained by condensa-
tion of chiral ketones, (1R)-(+)-camphor or (1R)-fenchone, with
aminoalkylpyridine derivatives in the presence of a catalytic
amount of BF3·OEt2 (Scheme 1) [15], while aminopyridine 2e was
formed by double alkylation with BuLi and MeI of the benzylic
position of 2a [15]. Ligand 2f was prepared by reaction of 8-
aminoquinoline with (1R)-(+)-camphor as previously described by
us [17], and now full characterized (Scheme 1).
The iminopyridines 4a,c–g were formed in one step by conden-
sation of pyridine-2-carboxaldehyde with the chiral amines 3a,c–g
in diethyl ether containing anhydrous K2CO3 at room tempera-
ture (Scheme 2) [13]. Analogously to ligands 4, the iminopyridines
5a–d,f,g were obtained by reaction of quinoline-8-carbaldehyde
with the chiral amines 3a–d,f,g (Scheme 2). All ligands 4 and 5 were
obtained as pure E isomers as determined by NOESY NMR spectra.
2.2.6. (E)-1-(Quinolin-8-yl)-N-((1R,2R,3S,5S)-2,6,6-
trimethylbicyclo[3.1.1]heptan-3-yl)methanimine
(5g)
Yield 83%; white solid mp 80–81 ◦C; [␣]D25 = +8.7 (c 1.0, CHCl3);
1H NMR (400.1 MHz, CDCl3): ı = 9.52 (s, 1H, NCH), 8.97 (dd, J = 4.2,
1.8 Hz, 1H, ArH), 8.48 (dd, J = 7.3, 1.4 Hz, 1H, ArH), 8.19 (dd, J = 8.3,
1.8 Hz, 1H, ArH), 7.89 (dd, J = 8.1, 1.4 Hz, 1H, ArH), 7.61 (t, J = 7.7 Hz,
1H, ArH), 7.44 (dd, J = 8.3, 4.2 Hz, 1H, ArH), 3.80–3.75 (m, 1H, CH),
2.45–2.33 (m, 2H), 2.25–2.17 (m, 1H), 2.01–1.98 (m, 2H), 1.92–1.89
(m, 1H), 1.32 (d, J = 9.5 Hz, 1H), 1.27 (s, 3H, CH3), 1.11 (s, 3H, CH3),
1.06 (d, J = 7.4 Hz, 3H, CH3); 13C NMR (100.6 MHz, CDCl3): ı = 155.7,
150.1, 146.8, 136.5, 133.6, 130.0, 128.4, 127.9, 126.7, 121.3, 70.6,
47.8, 43.6, 42.0, 39.1, 36.1, 34.3, 28.3, 23.7, 20.0; Anal. Calcd. for
C20H24N2: C, 82.15; H, 8.27; N, 9.58. Found: C, 82.61; H, 8.49; N,
9.86.
2.3. General procedure for the enantioselective allylic alkylation
reaction
H
O
H
N
Et2O, K2CO3
rt, 24 h
*R NH2
3a,c-g
In a typical procedure a solution of [Pd(␩3-C3H5)Cl]2 (4 mg,
2.5 mol%) and of the appropriate ligand (0.04 mmol, 10 mol%)
(L/Pd = 4/1) in CH2Cl2 (3 mL) was stirred at room temper-
*R
*R
N
N
4a,c-g
H
O
H
N
ature for 30 min. Then, 1,3-diphenylprop-2-enyl acetate
6
Et2O, K2CO3
rt, 24 h
*R NH2
3a-d,f,g
(100.9 mg, 0.4 mmol), dimethyl malonate (159.0 mg, 1.2 mmol),
N,O-bis(trimethylsilyl)acetamide (BSA) (244.0 mg, 1.2 mmol) and
CH3COOK (1.4 mg, 0.014 mmol, 3.5 mol%) were added in sequence.
The reaction was monitored by TLC analysis (hexane/diethyl
ether = 3:1). After the proper time (see Table 1), the reaction mix-
ture was diluted with ether and washed with an ice-cold saturated
NH4Cl solution. The organic phase was dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The residue
was purified by flash chromatography (hexane/diethyl ether = 3:1)
to afford 1,3-diphenylprop-2-enyl malonate 7. The enantiomeric
excess was determined by HPLC analysis using a Chiracel OD-H
column with hexane/IPA 90:10 as the eluent, 0.5 mL/min. Reten-
tion time: 11.9 min for the R enantiomer and 12.6 min for the S
enantiomer.
N
N
5a-d,f,g
d: R* =
H
H
H
H
Me
Me
Me
a: R* =
,
c: R* =
g: R* =
,
b: R* =
,
Ph
Me
H
Me
,
,
f: R* =
e: R* =
H
H
Scheme 2.

76
M. Solinas et al. / Journal of Molecular Catalysis A: Chemical 385 (2014) 73–77
Table 1
Allylic alkylation of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate (Scheme 3).a
Entry
Ligand
Time (h)
Conversion (%)b
Yield (%)c
ee (%)d
Configuratione
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2e
2f
4a
4c
4d
4e
4f
4g
5a
5b
5c
5d
5f
20
20
24
48
24
72
72
72
20
20
20
24
72
21
72
24
44
72
24
72
100
100
100
100
37
62
50
7
100
100
100
100
55
100
70
87
95
44
79
100
91
92
88
76
nd
23
30
nd
98
92
79
87
52
95
63
87
89
35
59
73
54
38
34
9
nd
62
20
nd
25
7
44
0
5
20
18
16
16
9
S
S
S
S
–
R
R
–
S
R
R
–
–
S
R
S
S
S
R
R
9
10
11
12
13
14
15
16
17
18
19
20
5g
5g
5
5
a
Reaction conditions: ligand (0.04 mmol, 10 mol%), [Pd(␩3-C3H5)Cl]2 (4 mg, 2.5 mol%), 1,3-diphenylprop-2-enyl acetate (0.4 mmol), CH2(COOMe)2 (1.2 mmol), N,O-
bis(trimethylsilyl)acetamide (BSA) (1.2 mmol) and KOAc (1.4 mg, 0.014 mmol, 3.5 mol%) in CH2Cl2 (3 mL) at room temperature.
b
Determined by 1H NMR of the crude reaction mixture.
Isolated yields.
Determined by chiral HPLC (see Section 2 for details).
The assignment is based on the sign of the optical rotation, see Ref. [20].
c
d
e
3.2. Palladium-catalyzed asymmetric allylic alkylation
On this bases, we examined the iminopyridine 2c in which an
ethylidene unit between the pyridine ring and the imino nitrogen
replaces the methylene spacer in 2a. This ligand that by coordi-
nation with the metal forms a six-membered chelate ring, namely
one more with respect to the related ligand 2a, gave a similar reac-
tive Pd-catalyst, but unfortunately a reduced stereodifferentiating
ability affording the product (S)-7 with 32% ee.
Then, as the ring-size control failed, we examined ligand 2d
that differs from 2a by the presence of a methyl group on the 6-
position of the pyridine ring. This ligand was selected since we
demonstrated that, in related oxazolinylpyridine ligands, bulkier
substituent than hydrogen on the 6-position of the pyridine ring
by increasing the stabilization of the sterically favoured diaste-
reomeric transition state (A or B, Scheme 3), gave a much higher
enantioselectivity than the related 6-unsubstituted ligand [21]. In
other words this substituent that is directed towards the substrate
should assist the substituent on the stereocenters of the iminopy-
ridine to improve the stereodifferentiating ability of the ligand.
Unfortunately, the use of ligand 2d was detrimental for both cat-
alytic activity and stereoselectivity, and (S)-7 was obtained with
only 9% ee.
Another modification of the ligand 1a was obtained by introduc-
ing two methyl groups on the bridged methylene carbon. The so
obtained iminopyridine 2e would result of increased stiffness with
respect to 2a, reducing in this way its conformational mobility in
the related Pd-complex. The change in the framework of 2a had a
double effect on the allylic reaction. Thus, ligand 2e reduced the
catalytic activity of the Pd-complex, producing only partial conver-
sion (62% after 72 h) of the starting material 6, but on the contrary
caused an increased enantiomeric excess of the product 7 (62% ee).
Moreover, the opposite enantiomer (R)-7 was surprisingly formed,
even though 2e shares the same stereochemical pattern of the other
related ligands 2a,c,d.
Since the use of ligands 2a,c and 2d afforded (S)-7 as the prevail-
ing enantiomer it is plausible that the reaction proceeds through
the same pathway, implicating the attack of the nucleophile on the
allylic termini of the same more abundant stereoisomer (b in A or
a in B). On the other hand, ligand 2e, afforded the opposite enan-
tiomer (R)-7, indicating a change of the steric course of the reaction
with a possible inversion of the equilibrium between diastereomers
As a model study of palladium catalyzed allylic substitutions,
the iminopyridines were assessed in the alkylation of 1,3-
diphenylprop-2-enyl acetate 6 with dimethyl malonate, following
a standard protocol that entails the use of [Pd(␩3-C3H5)Cl]2 as the
precatalyst and the generation of the nucleophile by in situ treat-
ment of dimethyl malonate with N,O-bis(trimethylsilyl)acetamide
(BSA) and potassium acetate in a methylene chloride solution at
room temperature (Scheme 3) [18].
Starting our investigation, we examined the iminopyridines
2a and 2b, derived from (1R)-(+)-camphor and (1R)-fenchone,
respectively. These ligands gave moderately reactive Pd-catalysts
requiring 20 h at room temperature to convert the starting mate-
rial 6 to dimethyl 1,3-diphenylprop-2-enylmalonate (S)-7 in 91 and
92% yield and with 54 and 38% enantiomeric excess, respectively
(Table 1).
The promising result obtained with 2a prompted us to con-
tinue this investigation by modifying the ligand framework. The
accepted mechanism for palladium catalyzed allylic substitutions,
which proceed through a meso ␩3-allyl intermediate, foresees that
the nucleophile attacks the allylic termini of two alternative diaste-
reomeric ␲-allyl palladium complexes, which interconvert through
a ␲–␴–␲ mechanism and are present at the equilibrium in a differ-
ent ratio (A ꢀ B, Scheme 4) [2,19]. Since, it has been demonstrated
that the stereoselectivity of the reaction is closely related to the
increase of the percentage of one of the two diastereomers, the
control of the steric ligand properties is of paramount importance.
A way to adjust the steric influence of the ligand can be achieved
by changing the ligand bite-angle or, in other words, the chelate
ring size of the metal-complex. As this parameter increases, the
substituents on the ligand are pushed towards the allylic termini
and the diastereomeric ratio between A and B is therefore modified,
influencing in this way the chiral recognition.
L*, [Pd(η3-C3H5)Cl]2, CH2Cl2
OCOCH3
Ph
CH(CO2CH3)2
Ph
*
Ph
Ph
CH2(COOCH3)2, BSA
6
7
Scheme 3.

M. Solinas et al. / Journal of Molecular Catalysis A: Chemical 385 (2014) 73–77
77
Ph
a
Nu
R1
N
Ph
+
Ph
Ph
b
Pd
Nu
Ph
Ph
OAc
CH(COOMe)2
R2
R2
n N
(S )-7
+
A
R1
Pd0
π−σ−π
N
a
Nu
b
R1
R2
R2
N
n
Ph
Ph
Ph
Nu
N
Pd
CH(COOMe)2
(R )-7
+
Ph
R2
R2
N
n
2a: n = 1, R1 = R2 = H
2c: n = 2, R1 = R2 = H
2d: n = 1, R1 = Me, R2 = H
2e: n = 1, R1 = H, R2 = Me
Nu = -CH(CO2Me)2
B
Scheme 4.
A or B, in this way favouring a transition state in which the nucle-
ophile attacks the diastereomers A or B via a or b, respectively.
To confirm this trend, the rigid ligand 2f in which the bridged
carbon is enclosed in a benzo-fused ring to the pyridine was pre-
pared. With this ligand, worse results concerning both catalytic
activity and enantioselectivity than with 2e were obtained (entry
7). Also in this case the configuration of the prevailing enantiomer
was (R).
Next, we turned our attention to the iminopyridines 4a,c–g
derived from pyridine-2-carboxaldehyde and a variety of chiral
amines (Scheme 2). These ligands afforded active Pd-catalysts giv-
ing 7 in high yield, but with poor enantioselectivity (Table 1). The
best enantioselectivity (44% ee) was obtained with the iminopyri-
dine 4f based on a camphane skeleton.
We also prepared the iminopyridine 5a from quinoline-
8-carbaldehyde with (S)-1-phenylethanamine (Scheme 2). This
ligand with the same substituent on the imino nitrogen with
respect to 4a, but forming with palladium a six-membered chelate
ring, gave a better catalytic activity and enantioselectivity than
4a (entry 14 vs 8, Table 1). Encouraged by this result, the
iminopyridines 5d,f,g were prepared (Scheme 2). Unfortunately,
disappointing results were obtained with these ligands, thus nei-
ther the yield nor the stereoselectivity were improved compared
to 5a (Table 1).
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A 378 (2013)
In conclusion, we have developed a new catalytic system
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with dimethyl malonate. This kind of ligands afforded the prod-
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Financial support from the University of Sassari is gratefully
acknowledged.