Steric and chelate ring size effects on the enantioselectivity in palladium-catalyzed allylic alkylation with new chiral P,N-ligands

Article abstract of DOI:10.1016/S0957-4166(00)00448-1

New chiral P,N-ligands derived from substituted pyridine and (S)-2,2′-binaphthol phosphorochloridite have been prepared and tested in asymmetric palladium-catalyzed allylic alkylations. The enantioselectivity was poorly dependent on the pyridine substitue

Full text of DOI:10.1016/S0957-4166(00)00448-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4753–4759
Steric and chelate ring size effects on the enantioselectivity
in palladium-catalyzed allylic alkylation with new chiral
P,N-ligands
Carmela Grazia Arena,* Dario Drommi and Felice Faraone
Dipartimento di Chimica Inorganica, Chimica Analitica e Chimica Fisica-Universita` di Messina, Salita Sperone,
31 Vill. S. Agata-98166 Messina, Italy
Received 25 October 2000; accepted 10 November 2000
Abstract
New chiral P,N-ligands derived from substituted pyridine and (S)-2,2%-binaphthol phosphorochloridite
have been prepared and tested in asymmetric palladium-catalyzed allylic alkylations. The enantioselectiv-
ity was poorly dependent on the pyridine substituent, instead, a chelate ring size effect was apparent.
© 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
During the last decade several chiral bidentate ligands have been found to achieve high levels
of stereocontrol in enantioselective palladium-catalyzed allylic substitution reactions.1 In this
field, we recently described the synthesis of a new series of chiral phosphine-phosphite and
pyridine-phosphite ligands2 (Fig. 1) and their use in the asymmetric allylic alkylation of
1,3-diphenylprop-2-enyl acetate with the nucleophile derived from dimethyl malonate.
Figure 1.
* Corresponding author. E-mail: c.arena@chem.unime.it
0957-4166/00/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00448-1

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C. G. Arena et al. / Tetrahedron: Asymmetry 11 (2000) 4753–4759
We found that the P,P-ligands (S)-1 and (S)-2 gave the substitution product with up to 71%
e.e., while no asymmetric induction has been achieved with P,N-ligand 3. This lack of
enantiomeric excess was attributed to the poor structural control with ligand 3 due to the lower
steric hindrance of the pyridine moiety with respect to the diphenylphosphino group in the
allylic intermediates [Pd(h3-PhCHCHCHPh(L–L%)]+ (L–L%=(S)-1–(S)-3). Indeed, as established
by NMR spectroscopy, the low steric demand of the pyridine moiety leads to fast exchange of
all the four possible configurational isomers of the Pd–allyl complexes present in solution. On
the other hand, only the exo–syn–syn and endo–syn–anti isomers were found in solution with
phosphine-phosphite ligands (S)-1 and (S)-2 which afforded the best e.e.s. Therefore, we verified
that the number and the relative concentrations of the Pd–allyl conformers present in solution
as intermediates in the allylic alkylation are a factor determining the enantioselectivity of the
process.
In light of these earlier results we have increased the steric hindrance of the pyridine–phos-
phite ligands by introducing different substituents on the 6-position in the pyridine moiety.
Furthermore, with the aim of obtaining a greater conformational rigidity, starting from
2-aminopyridine, we have also synthesized chiral P,N-ligands which form a five-membered
chelate ring with the metal center.
Here we report the preparation of these new P,N chiral ligands and their application in the
asymmetric palladium-catalyzed allylic alkylation.
2. Results and discussion
2.1. Ligands synthesis
Ligands (S)-4–(S)-6 (Fig. 2) were synthesized in good yields (78–80%) by reaction of the
corresponding (6-substituited-pyridin-2-yl)methanol with 1 equivalent of (S)-2,2%-binaphthol
phosphorochloridite in the presence of NEt3 at 0°C in toluene. All the ligands were obtained as
white moisture sensitive solids. The 31P{1H}NMR spectra of (S)-4–(S)-6, in C6D6, show a single
peak in the range 138.8–139.4 ppm as expected for phosphite compounds.2
Figure 2.
Ligands (S)-7 and (S)-8 (Fig. 3) were readily accessible in moderate to good yields (58–77%)
by reaction of the corresponding commercial 2-aminopyridine with the (S)-2,2%-binaphthol
phosphorochloridite in a 2.5:1 ratio at −10°C in toluene. In a particular case, the 2-aminopy-

C. G. Arena et al. / Tetrahedron: Asymmetry 11 (2000) 4753–4759
4755
ridine was also used as a base to remove the HCl formed in the reaction course. The
31P{1H}NMR spectra of (S)-7 and (S)-8, in C6D6, show a single peak in the range 146.5–147
ppm as expected for phosphoroamidite compounds.3
Figure 3.
2.2. Asymmetric allylic alkylation
These new chiral P,N-ligands were tested in the enantioselective palladium-catalyzed allylic
substitution of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate according to Trost’s
procedure.4 The results are summarized in Table 1.
All the catalytic systems Pd/L [(S)-4–(S)-8] afforded the dimethyl-1,3-diphenylprop-2-enyl-
malonate in high yields although the enantioselectivity was rather low (7–37%). However, it is
possible to draw some conclusions. The presence of a substituent in 6-position on the pyridine
ring seems to have little influence on the enantioselectivity of the allylic alkylation (entries 2–4).
Unexpectedly, the phenyl group greatly accelerates the reaction but the e.e. remains low (entry
4).
Table 1
Allylic alkylation of 1,3-diphenylprop-2-enyl acetate with dimethyl malonatea
Entry
Ligand
Time, h
Yieldb
% E.e.c
1
2
3
4
5
6
3
4
5
6
7
8
16
16
16
4
16
16
95
91
94
95
93
90
0
11 (S)
7 (S)
7 (S)
37 (S)
33 (S)
a [(h3-C3H5)PdCl]2 (0.5 mol%), ligand (1.25 mol%), H2C(COOMe)2 (3 equiv.) BSA (3 equiv.), KOAc (1 mol%),
CH2Cl2.5
b Yield of analytically pure product after column chromatography.
1
c Determined by H NMR spectroscopy (CDCl3/0.25 equiv. [Eu(hfc)3]).5

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Data obtained with ligands (S)-4–(S)-6 clearly show that Me, Br, and Ph groups in 6-position
on the pyridine ring are, in such cases, not sufficient to exert a steric control on the
palladium-catalyzed allylic alkylation of 1,3-diphenylprop-2-enyl acetate. In fact, as in the case
of [Pd(PhCHCHCHPh)(S)-3]+, NMR spectra of the allylic intermediates [Pd(PhCHCHCHPh)-
((S)-4–(S)-6)]+ proved that all four possible isomeric forms are present in the same concentra-
tion ratio and undergo fast exchange processes. Most probably, this is the reason for the modest
enantioselectivity observed. However, it cannot be excluded that the introduction on the
pyridine ring of a more bulky substituent than a tert-butyl group might improve the asymmetric
induction. Unfortunately, up to now we have not been able to prepare the 6-tert-butylpyridine-
phosphite ligand in good yields and high purity.
Ligands (S)-7 and (S)-8, forming five-membered chelate rings, are more effective for the
asymmetric induction than ligand (S)-3–(S)-6 forming a six-membered chelate (entries 1 and 5).
Besides, the chelate ring size shows a remarkable effect on the e.e. more than the introduction
of a substituent on the 6-position of the pyridine ring (entries 1, 2 and 5). Probably, with these
P,N-ligands, an increase in the rigidity of the intermediate Pd–allyl complex improves the
enantioselectivity of the reaction. With the aim of clarifying this aspect we studied by NMR
spectroscopy the behavior in solution of the p-phenylallyl-(S)-7–palladium complex.
31P{1H} NMR spectrum of [Pd(PhCHCHCHPh)(S)-7]+, 9, in chloroform-d solution showed a
broad signal at l 146.42 ppm indicating that exchange processes are present in solution. By
1
1
running H 2D NOESY and 13C, H correlation spectra6 it was possible to recognize in solution
four different isomers, but we were able to determine only the structures of the two major
conformers. The isomer present in greater amount (56%) was identified as endo–syn–syn–
[Pd(PhCHCHCHPh)(S)-7]+ (Fig. 4). In fact, the proton Ha at l 6.54 ppm (broad doublet)
showed an NOE with Hb (l 6.25 ppm, broad multiplet); the absence of any cross peaks between
Ha or Hb with Hc (l 6.45 ppm, broad triplet) was a further confirmation7 of the assigned
structure. The 13C NMR spectrum revealed allylic carbon resonances lying in a very narrow
range: Ca, l 127.37 ppm; Cb, l 126.86 ppm; Cc, l 114.37 ppm. The almost negligible chemical
shift difference between the two allylic terminal carbons Ca and Cb is typical for nuclei residing
in a similar chemical environment.8
Figure 4.

C. G. Arena et al. / Tetrahedron: Asymmetry 11 (2000) 4753–4759
4757
The second isomer (37%) presented a broad peak doublet at l 5.07 ppm assigned as H*a , a
broad multiplet at l 6.15 ppm, H*b , and a broad triplet at l 5.93 ppm, Hc*. The presence of an
NOE cross peak between H*a and Hc* led us to confirm an exo–syn–anti conformation for this
isomer. The 13C,1H correlation allowed us to assign allylic carbon atoms for this isomer: The
allylic 13C resonances had substantially different chemical shifts: C*a , l 74.10 ppm; Cb*, l 116.92
ppm; Cc*, l 97.42 ppm. These results let us conclude that between the two terminal allylic
carbons the more deshielded nucleus C*b is the preferred site for the nucleophilic attack in allylic
alkylation.8
As NMR studies demonstrated, the five-membered chelate ring increases the ratio of the two
Pd–allyl configurational isomers among the four possible9 formed in solution, but this is not
sufficient to obtain a high asymmetric induction.
3. Experimental
Solvents were dried by standard procedures. All experiments were performed under purified
argon. For column chromatography, silica gel 60 (220–440 mesh) purchased from Fluka was
used. 1D- and 2D-NMR experiments were carried out using a Bruker AMX R300 spectrometer.
1H NMR spectra were referenced to internal tetramethylsilane and 31P{1H} spectra to external
1
85% H3PO4. Standard pulse sequences were employed for H-2D-NOESY, 13C,1H-, 31P,1H-cor-
relation studies.10 The phase-sensitive NOESY experiments used mixing times of 0.8 s. Elemental
analyses were performed by Redox s.n.c., Monza, Milan.
3.1. (S)-2-(3,5-Dioxa-4-phosphacyclohepta[2,1-a;3,4-a%]dinaphthalen-4-yloxymethyl)-
6-methyl-pyridine 4
A solution of (6-methyl-pyridin-2-yl)methanol (0.215 g, 1.75 mmol) and Et3N (0.708 g, 7.00
mmol) in toluene (5 ml) was added dropwise to a solution of (S)-2,2%-binaphthol
phosphorochloridite10 (0.612 g, 1.75 mmol) in the same solvent (10 ml) at 0°C. The reaction
mixture was stirred overnight at room temperature and then the precipitate of Et3N·HCl formed
was removed by filtration. The toluene was evaporated from the filtrate. The residue was washed
1
with hexane (5 ml) and dried. A white solid was obtained in 78% yield (0.597 g, 1.36 mmol). H
NMR (C6D6) l 2.41 (s, 3H), 5.20 (m, 2H), 6.65 (d, 1H, J=6.0 Hz), 7.01–7.71 (m, 14H). 31P{1H}
NMR (C6D6) 139.4 (s). Anal. calc. for C27H20NO3P: C, 74.14; H, 4.61; N, 3.20. Found: C, 74.35;
H, 4.69; N, 3.14.
3.2. 2-Bromo-(S)-6-(3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a%]dinaphthalen-4-yloxy-
methyl)pyridine 5
This compound was obtained by an analogous procedure to 4, as a white solid, by reaction
of (6-bromopyridin-2-yl)methanol (synthesized by reduction of the corresponding aldehyde11)
(0.282 g, 1.50 mmol) and (S)-2,2%-binaphthol phosphorochloridite (0.525 g, 1.50 mmol). Yield:
1
90% (0.678 g, 1.35 mmol). H NMR (C6D6) l 5.03 (m, 2H), 7.13–7.68 (m, 11H), 7.97–8.08 (m,

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C. G. Arena et al. / Tetrahedron: Asymmetry 11 (2000) 4753–4759
4H). 31P{1H} NMR (C6D6) 138.1 (s). Anal. calc. for C26H17BrNO3P: C, 62.17; H, 3.41; N,
2.79. Found: C, 62.37; H, 3.34; N, 2.85.
3.3. (S)-2-(3,5-Dioxa-4-phosphacyclohepta[2,1-a;3,4-a%]dinaphthalen-4-yloxymethyl)-
6-phenyl-pyridine 6
This compound was obtained by an analogous procedure to 4, as a white solid, by reaction
of (6-phenylpyridin-2-yl)methanol12 (0.185 g, 1.00 mmol) and (S)-2,2%-binaphthol phospho-
1
rochloridite (0.350 g, 1.00 mmol). Yield: 85% (0.361 g, 0.85 mmol). H NMR (C6D6) l 5.24 (m,
2H), 7.01–7.80 (m, 14H), 8.08–8.16 (m, 2H). 31P{1H} NMR (C6D6) 138.8 (s). Anal. calc. for
C32H22NO3P: C, 76.95; H, 4.44; N, 2.80. Found: C, 76.77; H, 4.36; N, 2.74.
3.4. (S)-(3,5-Dioxa-4-phosphacyclohepta[2,1-a;3,4-a%]dinaphthalen-4-yl)-pyridin-2-yl-amine 7
A solution of (S)-2,2%-binaphthol phosphorochloridite (0.410 g, 1.17 mmol) in toluene (7 ml)
was added dropwise to a solution of 2-aminopyridine (0.275 g, 2.92 mmol) in the same solvent
(10 ml) at −10°C. The resulting solution was stirred overnight at room temperature and then the
solvent was vacuum evaporated. The pure ligand 7 was extracted by toluene/hexane (3:1) from
1
the resulting white powder. Yield 77% (0.368 g, 0.901 mmol). H NMR (C6D6) l 4.96 (s, 1H),
6.59–6.85 (m, 3H), 7.31–7.62 (m, 11H), 7.92–8.08 (m, 9H), 8.12 (d, J=6.0 Hz, 1H). 31P{1H}
NMR (C6D6) 146.5 (s). Anal. calc. for C25H17N2O2P: C, 73.52; H, 4.20; N, 6.86. Found: C,
73.23; H, 4.29; N, 7.02.
3.5. (4,6-Dimethyl-pyridin-2-yl)-(S)-(3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a%]dinaphthalen-
4-yl)-amine 8
This compound was obtained by an analogous procedure to 7, as a white solid, by reaction
of 4,6-dimethyl-pyridin-2-ylamine (0.275 g, 2.25 mmol) and (S)-2,2%-binaphthol phosphorochlo-
1
ridite (0.315 g, 0.90 mmol). Yield: 58% (0.228 g, 0.522 mmol). H NMR (C6D6) l 2.44 (s, 3H),
2.54 (s, 3H), 4.79 (s, 1H), 5.79 (s, 1H), 5.99 (s, 1H), 6.99–7.27 (m, 7H), 7.4–7.80 (m, 11H).
31P{1H} NMR (C6D6) 147.0 (s). Anal. calc. for C27H21N2O2P: C, 74.30; H, 4.85; N, 6.42. Found:
C, 74.45; H, 4.93; N, 6.37.
3.6. [Pd(p3-PhCHCHCHPh)((S)-7)]CF3SO3 9
A solution of 7 (0.255 g, 0.625 mmol) in CH2Cl2 (3 ml) was added to a stirred solution of
13
[Pd(h3-PhCHCHCHPh)(m-Cl]2 (0.164 g, 0.250 mmol) in the same solvent (10 ml). After ca. 30
min, AgCF3SO3 (0.130 g, 0.500 mmol) was added, and the precipitated AgCl filtered on Celite.
The filtrate was vacuum reduced to ca. 3 ml and addition of hexane (20 ml) gave a yellow solid.
1
Yield: 86% (0.364 g, 0.425 mmol). H (CDCl3): l 6.45 (br t, Hc), 6.05 (br d, Ha), 6.25 (br m, Hb)
5.93 (br t, Hc*), 5.07 (br d, Ha*), 6.15 (br m, H*b ). 31P {1H} (CDCl3): l 146.42 (br s). Anal. calc.
for C41H30F3N2O5PPdS: C, 57.45; H, 3.53, N, 3.27. Found: C, 57.56; H, 3.47 N, 3.20.

C. G. Arena et al. / Tetrahedron: Asymmetry 11 (2000) 4753–4759
4759
Acknowledgements
We thank MURST for financial support.
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