N-heterocyclic pyridylmethylamines: Synthesis, complexation, molecular structure, and application to asymmetric Suzuki-Miyaura and oxidative coupling reactions

Article abstract of DOI:10.1021/om200375s

The synthesis of N,N-bidentate ligands based on a π-deficient N-heterocyclic pyridylmethylamine core is described. The preparation and characterization of the corresponding N,N-ligand-palladium complexes in solution and the solid state are illustrated. Pd complexes showed a good yield and moderate catalytic activity (up to 40% ee) in the asymmetric Suzuki-Miyaura coupling reaction, leading to methoxybinaphthyl derivatives. The combination of N,N-pyridylmethylamines with cuprous iodide revealed effective catalytic systems in oxidative naphthol derivative coupling reactions, affording the corresponding binaphthyls in high yields and with enantioselectivities of up to 61%.

Full text of DOI:10.1021/om200375s

ARTICLE
pubs.acs.org/Organometallics
N-Heterocyclic Pyridylmethylamines: Synthesis, Complexation,
Molecular Structure, and Application to Asymmetric
SuzukiꢀMiyaura and Oxidative Coupling Reactions
Guillaume Grach,†,‡ Grꢀegory Pieters,† Aurelia Dinut,†,‡ Vincent Terrasson,† Raouf Medimagh,†
Alexandre Bridoux,† Vanessa Razafimahaleo,† Anne Gaucher,† Sylvain Marque,†
Jꢀer^ome Marrot,† Damien Prim,*,† Richard Gil,‡ Josꢀe Giner Planas,§ Clara Vi~nas,§
Isabelle Thomas,|| Jean-Philippe Roblin,|| and Yves Troin||
†Universitꢀe de Versailles, Saint-Quentin-en-Yvelines, Institut Lavoisier de Versailles (ILV), UMR CNRS 8180, 45 avenue
des Etats-Unis, 78035 Versailles, France
‡Equipe de Catalyse Molꢀeculaire, Institut de Chimie Molꢀeculaire et des Matꢀeriaux d’Orsay (ICMMO), UMR CNRS 8182, b^at. 420,
Universitꢀe Paris-Sud 11, 91405 Orsay Cedex, France
§Institut de Ciꢁencia de Materials de Barcelona (ICMAB-CSIC), Campus UAB, 08193 Bellaterra, Spain
Clermont Universitꢀe, ENSCCF, EA 987, LCHG, BP 10448, F-63000 Clermont-Ferrand, Ensemble scientifique des Cꢀezeaux, 24,
Avenue des Landais, BP10187, 63174 Aubiꢁere Cedex, France
S Supporting Information
b
ABSTRACT: The synthesis of N,N-bidentate ligands based on
a π-deficient N-heterocyclic pyridylmethylamine core is de-
scribed. The preparation and characterization of the corre-
sponding N,N-ligandꢀpalladium complexes in solution and
the solid state are illustrated. Pd complexes showed a good yield
and moderate catalytic activity (up to 40% ee) in the asym-
metric SuzukiꢀMiyaura coupling reaction, leading to methox-
ybinaphthyl derivatives. The combination of N,N-pyridylmethylamines with cuprous iodide revealed effective catalytic systems in
oxidative naphthol derivative coupling reactions, affording the corresponding binaphthyls in high yields and with enantioselectivities
of up to 61%.
’ INTRODUCTION
ligands were shown to be efficient in the preparation of various
biphenyls and 3-substituted indoles through SuzukiꢀMiyaura
couplings and FriedelꢀCrafts alkylations, respectively (Figure 1).
In the present paper, we describe the synthesis and character-
ization of the six new enantiopure N,N-bidentate ligands
L10ꢀL14 based on our previous N,N-pyridylalkylamine design
(Figures 2 and 3) and their palladium complexes. Various aspects
of the preparation and properties of racemic N,N-bidentate
ligands (L1ꢀL9) and their metal complexes, previously synthe-
sized by us (Figure 3),5ꢀ8 are also included in the paper for
comparison and summarization. We have studied the coordina-
tion chemistry of all these ligands in solution and the molecular
structures in the solid state for C4ꢀC6, C8, C9, and C14.
In addition, we describe the use of both ligands and complexes in
the stereoselective preparation of binaphthyl derivatives through
asymmetric Cu-promoted oxidative naphthol coupling and
Pd-assisted SuzukiꢀMiyaura coupling reactions, respectively
(Figure 2).
Pyridines bearing one methylamine pendant arm constitute an
appealing subclass of vicinal diamines that serve as efficient
pentadentate ligands. Especially valuable is the (2-pyridyl)
methylamine motif, which forms an ideal 1,2-N,N-bidentate
ligand. The association of several of such frameworks can be
found in bioinspired tetra- or pentadentate ligands that enable the
stabilization of metastable metallic species1 or mimic P-450 in vivo
oxidations.2 Tripodal ligands related to tris(pyridylmethyl)amine
(TPA), tris(pyridyl)methylamine (tpm), or bis(pyridylmethyl)
pyridine-2-carboxamide have recently received a great deal of
attention. Indeed, Cu, Re, Fe, and Zn complexes have been
obtained, characterized, and studied.3 Moreover, the (2-pyridyl)-
methylamine scaffold associated with a camphor substituent has
been recently used in efficient Cu-promoted Henry reactions.4
Despite increasing reports of both stoichiometric and catalytic
issues related to such ligands, there is a steady demand for
original, easily accessible, and flexible 1,2-N,N-bidentate ligands
capable of generating a large number of selective chemical
transformations. According to this general statement, we recently
reported the synthesis of new simple N,N-pyridylpiperidines and
N,N-pyridylalkylamines.5ꢀ8 Associated with Pd5 or Yb,6 such
Received: May 6, 2011
Published: July 06, 2011
r
2011 American Chemical Society
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Figure 1. N,N-bidentate pyridylamine and pyridylpiperidine ligands.
’ RESULTS AND DISCUSSION
Synthesis of Ligands. We first focused on the preparation of a
large panel of ligands. As illustrated in Figure 3, the multiple
modulation sites of the pyridylmethylamine central core are one
of the clear advantages of this ligand family. Indeed, substitutions
at the pyridine heterocycle, of the pendant methylene arm, and of
the second nitrogen atom account for the strong steric and
electronic modulations that may arise from the installation of
various additional groups at the ligand skeleton in order to finely
tune the ligand characteristics. As shown below, positions R to
the pendant arm nitrogen atom were assigned to as 1 and 10.
Most N-heterocyclic pyridylmethylamine ligands presented in
Figure 3 were easily obtained from common reactants in one or
two steps. Several strategies have been developed to obtain
ligands L1ꢀL14 depending on the commercial availability of
the reactants and their intrinsic reactivity, the targeted substitu-
ent, and the substitution pattern as well as the stereochemical
outcome in the preparation of nonracemic ligands.
As detailed in Schemes 1ꢀ4, ligands L1ꢀL9 have been
previously reported. This section intends to gather all prepara-
tion methods. Thus, ligands L2ꢀL4 were synthesized in two
steps according to previous studies (Scheme 1).5a,7 This strategy
allowed easy access to pyrimidine and pyrazine analogues. Ligand
L5, comprising a trialkylated nitrogen atom in the pendant arm,
was obtained through additional alkylation of L2.
Moving from a phenyl ring at the pendant arm to a larger
substituent was also examined. In this context, installation of a
large carboranyl cluster in ligand L6 required the modification of
the preparation sequence. Indeed, the joint presence of an
aminomethyl-o-carborane cluster and a pyridine heterocycle
was not trivial, and L6 was efficiently prepared by a two-step
procedure involving mesylation of the corresponding carboranyl
alcohol prior to nucleophilic amination, as shown in Scheme 2.8
We next focused on ligands that display any substitution at the
pseudobenzylic position of the pendant arm. Ligands L1 and
enantiopure L7 were thus prepared in one step by reductive
amination of pyridine-2-carboxaldehyde with the corresponding
amines in quantitative yields (Scheme 3).6,5
Figure 2. Asymmetric CꢀC bond formation using N-heterocyclic
pyridylmethylamine-based Cu and Pd complexes.
intermediate aldimines afforded the ligands L8,6 L11,6 and L12
with yields ranging from 49 to 74%. This reaction has proved to
be highly diastereoselective in the case of L14, thus leading to
(1S,10S)-L14 as the almost unique diastereomer (dr = 98/2).
Furthermore, to synthesize both the next diastereomer of L14
and ligand L10, we have used an in situ quenching (ISQ)
procedure,9 which involved the addition of n-BuLi to a mixture
of the corresponding imine and aryl bromide. The generated
aryllithium derivative is further directly trapped by the imine in
the reaction medium. This method led to (1R,10S)-L14 in 65%
yield (dr = 92/8), whereas ligand L10 was obtained in 33% yield.
All these methodologies allowed us to prepare a variously
substituted N,N-bidentate ligand family based on a pyridylalkyla-
mine core. Diastereomeric ligands L12 and L13 are inseparable, and
in the case of ligand L10 only one diastereomer could be isolated.
Fortunately, diastereomeric ligands L8, L9, and L11 could be
separated and isolated by column chromatography on silica gel.
The absolute configuration of each diastereomer of L8 was deter-
mined by comparison of their optical activity and NMR spectra with
literature data.10 In addition, the 1S,10Rabsolute configuration of the
second eluted diastereomer of L8 was confirmed by X-ray diffrac-
tion analysis of the corresponding Pd(II) complex (vide infra).
Configuration of the newly formed tertiary carbon center in L11 was
assigned according to L8 analytical data. The X-ray diffraction
analysis of the corresponding Pd(II) complexes allowed us to
unambiguously establish the absolute configuration of the 1R,10R
and 1S,10R diastereomers of L9. Finally, the 1R,10S absolute
configuration of L14 was again determined by X-ray diffraction
analysis of the corresponding Pd(II) complex.
Pyridine-based ligands L8ꢀL14 are more complex structures
than the former L1ꢀL7, as they simultaneously bear various
substituents at the pseudobenzylic position (Me, Ph, ferrocenyl)
and at the second nitrogen atom. Since all these ligands have
been obtained through formal addition of a nucleophile to an
aldimine or ketimine, several strategies were developed in order
to obtain nonracemic ligands and evaluate the influence of
stereogenic centers on asymmetric catalytic transformations
(vide infra).
Complexation. In order to illustrate the potential of this
family of ligands in coordination chemistry, we next turned our
attention to the synthesis of palladium complexes. Analysis both
in solution and in the solid state may allow us not only to confirm
privileged conformations and configurations of ligands and
complexes but also to gain additional structural information in
the catalysis context of this paper. Thus, ligands L1ꢀL14 were
treated with Na2PdCl4 in freshly distilled methanol at room
temperature according to standard conditions11 to give the
Ligands L96 and L13 were obtained in 90 and 92% overall
yields, respectively, by reduction of the corresponding ketimines
with sodium borohydride (Scheme 4). The addition of methyl-
magnesium bromide or phenyllithium to the corresponding
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Figure 3. N-Heterocyclic pyridylmethylamine ligands L1ꢀL14.
Scheme 1. Hetero-Biarylmethylamine Ligands L2ꢀL55a,7
Scheme 4. Preparation of Pyridylamine Ligands L8ꢀL146
Scheme 2. 2-AminomethylpyridineꢀCarborane Ligand L68
Scheme 3. Preparation of Pyridylamine Ligands L1 and
L75c,6
It is noteworthy that the substituents installed at the pyridyl-
methylamine core did not affect the complexation yields. In all
cases, the desired complexes were easily purified by simple
filtration through a silica gel pad and were perfectly air-stable,
both in the solid state and in solution. The complexation has
resulted in the creation of a chiral center on the pendant arm
expected Pd(II) complexes in yields ranging from 71% to
quantitative yields (Scheme 5). As shown in Scheme 5, com-
plexes C2ꢀC6 have been previously reported.
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Scheme 5. Preparation of Palladium Complexes
nitrogen atom that could adopt R and S configurations (see the
Supporting Information for an illustration). Depending on the
nature of the R1 substituent on the ligand, the complexation
reaction may occur selectively or not. When there is no chiral
center at the pseudo-benzylic position (R1 = H), there is no
control of the chirality on the nitrogen atom and consequently
the complexation reaction occurs in a nonselective way. Indeed,
in the case of achiral ligand L1 the complexation process afforded
a racemic mixture of two palladium complex enantiomers C1.
For chiral ligand L7, two enantiopure diastereomers C7 were
obtained after complexation, evidenced by the presence of two
sets of signals (dr = 50/50) in the 1H NMR spectra.
On the other hand, the presence of a stereocenter at a
pseudobenzylic position (R1 ¼ H) seems to control the central
chirality on the nitrogen atom. The complexation reaction then
occurred in a diastereoselective way. Thus, complexes C2ꢀC6,
prepared from racemic ligands L2ꢀL6, were obtained as single
rac diastereomers, since only one set of signals was found in the
1H NMR spectra. Furthermore, the complexation reaction
involving the enantiopure ligands (1R,10R)-L8, (1S,10R)-L8
(see the Supporting Information), (1R,10R)-L9, (1S,10R)-L9,
L10a, (1S,10S)-L14, and (1R,10S)-L14 apparently afforded only
one enantiopure diastereomer complex in each case. Interest-
ingly, diatereomeric ligands L12 and L13 were inseparable and the
reaction with Na2PdCl4 led to the corresponding complexes C12
and C13 as a mixture of two enantiopure diastereomers. Fortu-
nately, diatereomeric complexes C13 could be separated by
column chromatography on silica gel; the C13a and C13b
notations are relative to the first and second eluted diastereomers.
All complexes have been fully characterized by NMR spectrosco-
py, the spectroscopic data being in agreement with their respective
structures.
Coordination of both nitrogen atoms of the ligand has been
confirmed by a characteristic positive shielding observed be-
tween the aforementioned probe protons of ligands L and those
of their corresponding complexes C, regardless of the hetero-
cycle core and the presence of additional substituents on the
methylamine fragment.
Molecular Structures. As mentioned above, there are three
sources of chirality in complexes C2ꢀC6 that could lead, in principle,
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Table 1. Selected Bond Distances (Å), Bond Angles (deg), and Torsion Angles (deg) for Complexes C2 and C4ꢀC6a
bond distance
Cl1ꢀPd
bond angle
b
compd
R1
Ph
R2
N1ꢀPd
N2ꢀPd
Cl2ꢀPd
N1PdN2
N1CC(R1)N2
C2
C4c
H
H
2.021(2)
2.024(7)
2.027(5)
2.020(2)
2.030(2)
2.031(2)
2.043(7)
2.022(8)
2.083(2)
2.049(3)
2.2819(6)
2.281(2)
2.278(2)
2.2931(7)
2.2887(8)
2.303(6)
2.289(2)
2.294(3)
2.301(7)
2.288(8)
81.49(8)
82.0(3)
82.3(3)
82.12(8)
81.1(1)
(23.1(2)
(34.9(9)
(27.9(9)
(29.4(3)
(37.0(3)
Ph
C5
C6
Ph
Me
H
Carb.
a See structure given above the table for nomenclature. b Positive (+) and negative (ꢀ) torsion angles correspond to the λ and δ isomers, respectively.
c There are two independent molecules in the asymmetric unit.
to eight different diateroisomers. The pseudo-benzylic carbon and
coordinated amine nitrogen atom are chiral centers that can adopt R
and S configurations, giving rise to four possible diastereomeric pairs
(RCRN, RCSN, SCRN, and SCSN; Supporting Information). Forma-
tion of enantiomeric pairs of the same configuration (RCRN and
SCSN) are disfavored due to the steric hindrance of the substituents at
both the pseudo-benzylic carbon and the benzyl substituent at
nitrogen (Supporting Information). The other source of chirality is
the nonplanar chelating ring that adopts two conformations: δ and λ
(Supporting Information). In fact, crystal structures for complexes
C2 and C4ꢀC6 contain racemic mixtures of RCSNλ and SCRNδ
diastereoisomers, exclusively. Although these structures have been
reported separately over several papers,5a,7,8 no discussion on the
configuration of the chiral centers was given, nor was a comparison
between them provided. Thus, we will compare and discuss all
structures in this paper. The molecular structures for the latter
complexes are included in the Supporting Information, and selected
bond lengths and angles are given in Table 1.
Scheme 6. Possible Configurations for Complex C9
As previously reported,5a the chelating ligands in complexes
C2 and C4ꢀC6 bind to the Pd through a pyridyl donor N1 and a
secondary amine donor N2, giving a puckered five-membered
ring. The coordination sphere at Pd is close to square planar, and
the PdꢀN(pyridine) bond distances are significantly shorter
than the PdꢀN(secondary amine) distances. The torsion angles
N1CC(R1)N2 (Table 1) clearly show the coexistence of both the
λ and δ isomers for these complexes. Interestingly, the fact that
only the racemic mixtures of RCRNλ and SCSNδ diastereoisomers
are found in the solid state suggests that these are the most stable
diastereomers in complexes C2 and C4ꢀC6.
aforementioned steric interactions. Therefore, only configura-
tions RCSNRCδ and RCSNRCλ are expected to be stable. From a
similar reasoning for complexation of (1S,10R)-L9 to Pd, we
could expect the formation of the most stable SCRNRCδ and
SCRNRCλ diastereoisomers. Very interestingly, crystal structures
for complexes C9, derived from (1R,10R)-L9 or (1S,10R)-L9,
contains exclusively the pure RCSNRCλ and SCRNRCδ diaste-
reoisomers, respectively (vide infra).
The molecular structures of complexes (1S,10R)-C8, (1R,10R)-
C9, and (1S,10R)-C14 have been now determined by X-ray
diffraction studies (Figure 4). Crystal data and details of the
structure determination for the new compounds are given in the
Supporting Information, and selected bond lengths and angles
for all related complexes are given in Table 2. For comparison,
the crystal structure for (1S,10R)-C9, previously reported by us,6
is also included in Figure 4, Table 2, and the discussion below.
Complexes (1S,10R)-C8, (1R,10R)-C9, and (1S,10R)-C14 all
crystallized in the noncentrosymmetric P212121 space group and
are diastereomerically pure, as shown by the nearly zero Flack
parameter (Supporting Information). The previously reported
(1S,10R)-C96 crystallized in the noncentrosymmetric P61 space
group and showed a Flack parameter of 0.08(4). As in the related
complexes C2 and C4ꢀC6, the chelating ligands in C8, C9, and
C14 bind to the Pd through a pyridyl donor N1 and a secondary
amine donor N2, giving a puckered five-membered ring.
In complexes C8ꢀC10 and C12ꢀC14 there are 4 sources of
chirality that could lead, in principle, to 16 different diastereo-
isomers. These complexes contain two chiral carbons, the
coordinated amine nitrogen atom, and the two possible con-
formations (δ and λ). However, since both carbon stereo-
centers have been fixed in ligands L8, L9, and L14, the number
of diastereoisomers are greatly reduced in their metal complexes
C8, C9, and C14. Let us consider as an example complex C9
(Scheme 6), for which X-ray structures for two pure diastereo-
isomers have been determined (vide infra). Complexation of
(1R,10R)-L9 to Pd could afford, in principle, four enantiomers
(RCRNRNδ, RCRNRCλ, RCSNRCδ, and RCSNRCλ). An examina-
tion of Scheme 6 clearly shows that the same configuration at the
benzylic and contiguous nitrogen is not favored due to the
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The coordination sphere at Pd is close to square planar, the
largest deviation of Cl1, Cl2, N1, and N2 from their mean plane
being 0.058 Å. As in the previous complexes, the PdꢀN-
(pyridine) bond distances are significantly shorter than the
PdꢀN(secondary amine) distances. The torsion angles N1CC-
(R1)N2 (Table 2) clearly show that only one of the two possible λ
or δ isomers is found in these complexes. Thus, the solid-state
configurations for these complexes are as follows: (SCRNRCδ)-
C8, (RCSNRCλ)-C9, (SCRNRCδ)-C9, and (RCRNSCλ)-C14.
Another interesting feature of the molecular structures for
these complexes is that all, except that for C6, show intramole-
cular πꢀπ interactions between the azaheterocycle and the
pendant arm substituent of the secondary amine (Figure 4,
Table 3, and the Supporting Information). It is noteworthy that
whereas most of the complexes show centroid-to-centroid dis-
tances between 3.8 and 4.0 Å and interplanar angles of 28ꢀ34°,
those for (RCSNRCλ)-C9 are 3.6 Å and 21.0°, respectively.
Although solid stateꢀliquid state conformations may differ, the
presence of intramolecular πꢀπ interactions in most of the solid-
state structures suggests that this is an energetically favored
conformation and thus it could be also present in solution.
Catalytic Studies. Asymmetric SuzukiꢀMiyaura Coupling.
Transition-metal-catalyzed bond formation has become a power-
ful chemical tool over the last decades. Among these catalyzed
transformations, the SuzukiꢀMiyaura reaction can be consid-
ered as one of the most popular and general ways to create
carbonꢀcarbon bonds and thus has found widespread applica-
tions in organic synthesis.12 We previously reported the efficient
combination of L1 or racemic ligands L2ꢀL6 and Na2PdCl4 for
SuzukiꢀMiyaura couplings, allowing us to prepare biaryl pro-
ducts in good yields.5a,4b,8 Although axially chiral biaryls are
present in numerous natural products and constitute an impor-
tant class of ligands for asymmetric catalysis, there are few reports
to date dealing with asymmetric biaryl syntheses involving
SuzukiꢀMiyaura cross-coupling reactions. Most of the examples
leading to axially chiral biaryl compounds,13 with enantiomeric
excesses from moderate to high, concern the use of chiral
palladiumꢀphosphine complexes as catalysts.14,15 Recent note-
worthy examples have been reported separately by Fujihara16 and
Uozumi,17 who showed that palladium nanoparticles stabilized
by a chiral phosphine and a recyclable palladium complex of a
polymer-supported chiral imidazoindole phosphine ligand can
effectively catalyze the asymmetric SuzukiꢀMiyaura reaction
with excellent selectivities in some cases. The most recent studies
described the use of NHCs (N-heterocyclic carbenes)18 and
ADCs (acyclic diainocarbenes)19 as chiral ligands and also the
use of unsymmetrical chiral PCN pincer palladium complexes,20
but in all cases the enantiomeric excess remained modest
(<39%). In this context, there is a steady demand for alternative,
new, easy to prepare, stable, and efficient catalytic systems. The
determination of a robust ligand arises from an overall compro-
mise between several significant criteria. If the whole efficiency of
the catalytic system (catalyst loading, yields, conversion, etc.) is a
key parameter, rapid access to the ligand, stability of both ligand
and transition-metal complex, a common starting material, and
ease of purification should also be taken into account. According
to these guidelines, we wish to report the first example of
asymmetric Suzuki coupling catalyzed by chiral, air-stable, easy
to prepare and handle palladium N-heterocyclic pyridylmethy-
lamine complexes.
Figure 4. Molecular structures of C8, C9, and C14 showing the
intramolecular πꢀπ interactions, with thermal ellipsoids set at the 50%
probability level. No other isomers are present in the crystals (see text).
Table 2. Selected Bond Distances (Å), Bond Angles (deg), and Torsion Angles (deg) for Complexes (1S,10R)-C8, (1R,10R)-C9,
(1S,10R)-C9, and (1S,10R)-C14a
bond distance
Cl1ꢀPd
bond angle
N1CC(R1)N2
b
compd
N1ꢀPd
N2ꢀPd
Cl2ꢀPd
N1PdN2
confign
C8
2.025(2)
2.020(2)
2.031(3)
2.020(1)
2.043(2)
2.038(1)
2.066(2)
2.043(1)
2.2822(6)
2.2851(5)
2.279(1)
2.3103(6)
2.3090(5)
2.3092(7)
2.3031(6)
81.99(7)
82.47(6)
81.86(9)
82.30(5)
ꢀ32.6(2)
+35.5(2)
ꢀ27.6(4)
+31.0(2)
SCRNRCδ
RCSNRCλ
SCRNRCδ
RCRNSCλ
C9
C9
C14
2.2986(7)
a See the structure given above the table for nomenclature. b Positive (+) and negative (ꢀ) torsion angles correspond to the λ and δ isomers, respectively.
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Table 3. Intramolecular AreneꢀArene Packing Geometries (Distances in Å and Angles in deg), Involved in Complexes C2,
C4ꢀC6, (SCRNRCδ)-C8, (RCSNRCλ)-C9, (SCRNRCδ)-C9, and (RCRNSCλ)-C14a
C2
C4
C5
C6
C8 (SRRδ)
C9 (RSRλ)
C9 (SRRδ)
C14 (RRSλ)
db
3.956
3.714
3.875
27.71
31.43
3.797
5.900
3.762
3.614
3.811
3.795
interplanar anglec
32.25
33.91
27.97
21.08
30.17
33.59
a See structure at the top of the table for nomenclature. b Ring centroid to ring centroid distance. c Angle between planes containing the aromatic rings.
Table 4. Asymmetric Suzuki Coupling Reactiona
entry
R1
Me
R2
Ph
R3
cat.
conversn (%)b
17/18b
yield of 17 (%)c
ee of 17 (%)d
1
Me
Me
Ph
Ph
Fc
(1R,10R)-C8
(1S,10R)-C8
(1R,10R)-C9
(1S,10R)-C9
C10a
60
86
53/47
79/21
77/23
74/26
67/33
80/20
88/12
9/91
25
57
75
70
45
70
58
11 (S)
11 (R)
40 (S)
20 (R)
33 (S)
35 (S)
8 (R)
2
Me
Ph
3
Me
Ph
100
100
76
4
Me
Ph
5
Me
Ph
6
Me
1-Np
1-Np
Ph
Ph
Ph
Ph
Ph
C13a
100
77
7 e
8 f
9 f
Me
C13b
CH2OH
CH2OH
(1S,10S)-C14
(1R,10S)-C14
87
36 (S)
27 (R)
Ph
76
12/88
a Reactions were carried out with 5 mol % palladium complex, 15 (0.226 mmol), 16 (0.452 mmol), and Cs2CO3 (0.904 mmol) in 2.5 mL of solvent
(toluene/EtOH/H2O = 1/1/0.5) at 80 °C for 24 h. b The conversion was determined by 1H NMR on the crude product. c Isolated yield. d Determined
by chiral HPLC analysis (see the Supporting Information). e The reaction time was 48 h. f The pure product was not isolated.
We focused our study on chiral palladium catalysts bearing two
stereocenters such as C8ꢀC10, C13, and C14. The reaction of
1-bromo-2-methoxynaphthalene (15) with 1-naphthaleneboro-
nic acid (16) was chosen as the model system. The experiments
were performed in a toluene/ethanol/water mixture at 80 °C,
using Cs2CO3 as base and 5 mol % of the [PdCl2-pyridyl-
methylamine] species C8ꢀC10, C13, and C14 as catalysts, as
is shown in Table 4. It should be noted that both diastereomers of
C8 provided the binaphthyl product 18 with the same level of
enantioselectivity but with the opposite configuration, showing
the importance of the stereocenter bearing the R3 substituent to
the enantioselectivity. Complete conversions were observed with
both diastereomer complexes (1R,10R)-C9 and (1S,10R)-C9
(entries 4 and 5), the binaphthyl compound 17 being isolated
in good yield. The first diastereomer (1R,10R)-C9 allowed
us to reach a promising 40% ee in favor of the S enantiomer
(entry 3), while the second diastereomer (1S,10R)-C9 provided
an enantioselectivity of 20% in favor of the opposite enantiomer.
These results clearly demonstrate the crucial role played by the
pseudo-benzylic stereocenter and the pendant arm nitrogen
atom in the enantiomer-discriminating step. Further screening
involving the use of catalysts (1S,10S)-C14 and (1R,10S)-C14
bearing a tridentate ligand led to the desired product 17 with
moderate selectivities of 36 and 27%, respectively, albeit in poor
yields (entries 8 and 9). Although we have no clear explanation
for the loss of stereoselectivity, intervention by the additional
hydroxyl group during the catalytic process seems likely detri-
mental to the overall catalytic efficiency of C14.
Although the formation of side product 18 during the catalytic
sequence could not be avoided, reactions conducted at 80 °C
afforded the target 17 in each case as the major product.
However, the presence of the protodehalogenation side product
18 appears detrimental to a high catalytic compromise in the
asymmetric Suzuki coupling context. The stereochemical out-
come of the catalytic process seems to be influenced by the
configuration of the pseudo-benzylic center. The presence of a
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Table 5. Oxidative Biaryl Coupling
a Determined by 1H NMR. b Isolated yield. c Determined by chiral HPLC analysis (see the Supporting Information). d No conversion was observed
at 40 °C after 48 h. The reaction was carried out at 70 °C for 4 days.
phenyl or naphthyl group seems crucial, as best results in both
yields and ee's were obtained using the C13 and C9 catalytic
systems. In addition, it is worth noting that complex C9, showing
the shortest intramolecular πꢀπ stacking interaction (Table 3)
with centroid-to-centroid distance (3.6 Å) and the shortest
interplanar angle (21.0°), exhibited the highest ee in the asym-
metric Suzuki coupling reactions tested in this work.
Disappointingly, binaphthol 21 was obtained in good yield but
with a very low ee using ligand L7 (entry 1). The enantiopure
diastereomeric ligands (1S,10R)-L8 and (1R,10R)-L8 showed im-
proved results, affording the expected binaphthyl product in both
good yields (78ꢀ84%) and ee's (25ꢀ42%). As already observed,
moving from (1S,10R)-L8 to (1R,10R)-L8 generated the opposite
senses of induction (entries 2 and 3), clearly confirming that the
pseudo-benzylic stereogenic center plays a crucial role in the chiral
information transfer. The diastereomeric ligands (1S,10R)-L9 and
(1R,10R)-L9 both led to excellent or quantitative yields but were
almost ineffective or only provided a moderate ee of 37% (entries 4
and 5). Using ligand L10a, bearing a ferrocenyl substituent, afforded
fair results, providing 50% isolated yield for 51% conversion and an
encouraging 61% selectivity. In contrast, no traces of binaphthol 21
could be observed using L14, even after a prolonged reaction course
(entry 7). This might be attributed to the presence of an additional
coordinating hydroxyl group detrimental to the optimal coordina-
tion mode invoked by Kozlowsky some years ago.21 Finally,
attempts to improve the selectivity by using (1S,10R)-L11 or
(1R,10R)-L11, based on a 6-methylpyridine core or phenylglycinol
fragment, respectively, failed. In the case of L11, binaphthol 21
could be isolated in 81% yield (entry 8), but the presence of an
additional methyl group at the pyridine heterocycle proved detri-
mental to the enantioselectivity.
Oxydative Biaryl Coupling. We next turned our attention to
the naphthol oxidative coupling reaction, which represents an
elegant alternative to Suzuki coupling for the synthesis of
symmetrical binaphthyl compounds. Moreover, the asymmetric
oxidative coupling of naphthols is particularly adapted to the
synthesis of chiral biaryl natural products that incorporate a
binaphthyl unit such as hypocrellin, nigerone, calphostine D,
cercosporin, and phleichrome as well as numerous analogues.21
Current catalysts for asymmetric oxidative naphthol coupling are
copperꢀamine complexes.22 An enantioselective study was in-
itially reported in the presence of stoichiometric copper(II)
complexes of chiral amines, such as sparteine and R-methyl-
benzylamine.23 Further development was made by using catalytic
amounts of proline-derived diamines and copper(I), but the
enantioselectivity still remained moderate.24 Better results were
obtained using 1,5-diaa-cis-decalin21 and mono-N-alkylated
octahydrobinaphthyl-2,20-diaine (H8-BINAM)25 as chiral diaine
ligands. In the context of N-heterocyclic pyridylmethylamines, we
started to examine the Cu-catalyzed enantioselective oxidative
coupling of 3-hydroxy-2-naphthoate ester 20 to binaphthol 21 in
the presence of chiral N-heterocyclic pyridylmethylamines L7ꢀL9,
L10a, and L11. The chiral catalytic systems were prepared in situ
from CuI (10 mol %) and pyridylmethylamines (10 mol %) in
dichloroethane (DCE). The experiments were performed at 40 °C
under an oxygen atmosphere. Reaction times were not optimized
and were extended to 48 h to maximize conversions (Table 5).
’ CONCLUSION
In conclusion, we have described the synthesis of N,N-
bidentate ligands based on a π-deficient N-heterocyclic pyridyl-
methylamine core. NMR analysis in solution and X-ray in the
solid state revealed the favored combination of configurations
due to the selective complexation process. Moreover, the pre-
sence of privileged conformations λ and δ were confirmed by
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X-ray data in the solid state. Starting from two fixed configura-
tions at both carbon atoms, the selective complexation induces
the absolute configuration of the nitrogen atom and the chiral
conformation (λ or δ) of the metallacycle. The use of Pd
complexes in asymmetric SuzukiꢀMiyaura reactions afforded
binaphthyls in 40 ee’s. In addition, the combination of N,N-
pyridylmethylamines and Cu proved efficient in the oxidative
coupling reactions of binaphthols, leading to binaphthyls in high
enantioselectivities (61%). Results disclosed in this paper high-
light the crucial role played by the pendant arm nitrogen atom
and the substituent of the pseudo-benzylic position in asym-
metric CꢀC bond formation. In addition, they evidence the
beneficial contribution of the presence of aromatic groups in the
Pd complexes, in which centroid-to-centroid distances and
interplanar angles are minimized.
(dd, J = 2.4, 1.2 Hz, 1H. Cp), 4.07ꢀ3.98 (m, 3H, Cp), 3.94 (s, 5H, Cp),
3.43ꢀ3.31 (m, 1H, CHꢀN), 2.66 (dd, J = 7.2, 5.7 Hz, 1H, NH), 1.26 (d,
J = 6.6 Hz, 3H, Me). 13C NMR (CDCl3, 75 MHz): δ 163.31 (Cquat, Ar),
149.18 (Ar), 145.50 (Cquat, Ar), 136.11 (Ar), 128.53 (2C, Ar), 127.03
(Ar), 126.88 (2C, Ar), 122.45 (Ar), 121.97 (Ar), 91.89 (Cquat, Cp),
68.51 (5C, Cp), 67.85 (Cp), 67.33 (Cp), 67.11 (Cp), 66.67 (Cp), 60.64
(CHꢀN), 55.77 (CHꢀN), 24.67 (Me). HRMS (ESI): calcd for
C24H25N2Fe (MH+) 397.1367, found 397.1349.
The second diastereomer was obtained as a mixture with several
unidentified byproducts.
Synthesis of N-[(6-Methylpyridin-2-yl)(phenyl)methyl]-
N-[(10R)-10-phenylethyl]amine (L12). A solution of 6-methylpyr-
idine-2-carboxaldehyde (600 mg, 4.95 mmol) and (R)-1-phenylethyla-
mine (600 mg, 4.95 mmol) in dry THF (25 mL) was stirred at room
temperature over anhydrous MgSO4 for 24 h. The reaction mixture was
filtered through a pad of Celite and washed with DCM, and the solvents
were removed under vacuum to yield the corresponding imine (100%,
1.13 g).
’ EXPERIMENTAL SECTION
To a stirred solution of the crude imine (400 mg, 1.78 mmol) in dry
Et2O (14 mL) at 0 °C was added dropwise PhLi (2.08 mL, 3.74 mmol,
1.8 M solution in dibutyl ether). The mixture was stirred at room
temperature for 20 h, and the reaction was quenched by adding water.
The aqueous layer was extracted with Et2O, and the combined organic
layers were dried over MgSO4, filtered, and concentrated under vacuum.
The crude product was purified by flash chromatography on silica gel,
using petroleum ether/ethyl acetate (95/5) as eluent, to afford an
inseparable mixture of the two desired diastereomers (dr = 54/46,
74%, 397 mg) as a yellow solid. 1H NMR (CDCl3, 300 MHz): δ 7.37
(t, J = 7.6 Hz, 1H, Ar major), 7.30ꢀ7.03 (m, 21H, Ar major and minor),
6.97 (d, J = 7.7 Hz, 1H, Ar minor), 6.88 (d, J = 7.6 Hz, 1H, Ar minor),
6.81 (d, J = 7.6 Hz, 1H, Ar major), 6.72 (d, J = 7.7 Hz, 1H, Ar major),
4.66 (s, 1H, CHꢀN minor), 4.57 (s, 1H, CHꢀN major), 3.56 (q, J = 6.7
Hz, 1H, CHꢀN major or minor), 3.55 (q, J = 6.6 Hz, 1H, CHꢀN major
or minor), 2.85 (br s, 2H, NH major and minor), 2.45 (s, 3H, Me major),
2.44 (s, 3H, Me minor), 1.31 (d, J = 6.7 Hz, 3H, Me major), 1.28 (d, J =
6.6 Hz, 3H, Me minor). 1H NMR ([D6]DMSO, 300 MHz) δ 7.64 (t, J =
7.6 Hz, 1H, Ar minor), 7.55 (t, J = 7.7 Hz, 1H, Ar major), 7.39ꢀ7.12
(m, 22H, Ar major and minor), 7.08 (d, J = 7.5 Hz, 1H, Ar minor), 7.03
(d, J = 7.5 Hz, 1H, Ar major), 4.61 (s, 1H, CHꢀN minor), 4.56 (s, 1H,
CHꢀN major), 3.60ꢀ3.44 (m, 2H, CHꢀN major and minor), 3.20
(br s, 2H, NH major and minor), 2.40 (s, 3H, Me minor), 2.40 (s, 3H,
Me major), 1.29 (d, J = 6.6 Hz, 3H, Me major), 1.28 (d, J = 6.6 Hz, 3H,
Me minor). 13C NMR (CDCl3, 75 MHz): δ 161.69 (Cquat, Ar), 161.47
(Cquat, Ar), 158.14 (Cquat, Ar), 157.70 (Cquat, Ar), 145.76 (Cquat, Ar),
145.49 (Cquat, Ar), 143.47 (Cquat, Ar), 142.86 (Cquat, Ar), 136.52 (Ar),
128.46 (Ar), 128.44 (Ar), 128.38 (Ar), 128.22 (Ar), 127.68 (Ar), 127.17
(Ar), 126.97 (Ar), 126.94 (Ar), 126.84 (Ar), 121.47 (Ar), 121.29 (Ar),
119.62 (Ar), 119.00 (Ar), 65.06 (CHꢀN), 64.79 (CHꢀN), 55.74
(CHꢀN), 54.89 (CHꢀN), 24.76 (Me), 24.70 (Me), 24.68 (Me),
24.34 (Me). HRMS (ESI): calcd for C21H23N2 (MH+) 303.1861, found
303.1850.
Synthesis of N-[(Pyridin-2-yl)(phenyl)methyl]-N-[(10R)-10-
phenylethyl]amine (L13). A solution of 2-benzoylpyridine (1.00 g,
5.46 mmol), (R)-1-(naphthalen-1-yl)ethylamine (0.935 g, 5.46 mmol),
and 4-methylbenzenesulfonic acid (104 mg, 0.546 mmol) in toluene
(25 mL) was refluxed for 40 h using a DeanꢀStark apparatus. After the
mixture was cooled, the solvent was removed and the residue was dried
under vacuum. The crude imine was dissolved in MeOH (30 mL), and
sodium borohydride (207 mg, 5.46 mmol) was added portionwise at
0 °C. The mixture was stirred overnight at room temperature, and the
reaction was quenched by adding saturated aqueous NH4Cl. The
aqueous layer was extracted with EtOAc. The combined organic layers
were washed with a saturated aqueous NaCl solution, dried over MgSO4,
filtered, and concentrated under vacuum. The crude product was
General Comments. All manipulations were carried out under an
atmosphere of argon in round-bottomed flasks equipped with magnetic
stirring. DCM, DCE, and toluene were distilled over CaH2. THF and
Et2O were distilled over sodium metal, and MeOH was distilled over
Mg/I2. 2-Pyridyl-o-carboranylmethanol26 and ligands L1,5c L2ꢀL5,5a
L6,8 L7ꢀL96, and L116 as well as complexes C2ꢀC55a and C68 were
prepared according to our previously described procedures. The crude
products were purified by column chromatography using Merck Kie-
selgel 60 silica gel. 1H and 13C NMR spectra were recorded on Bruker
AM 300 and DPX 200 spectrometers and referenced to CDCl3 or
[D6]DMSO, unless otherwise noted. FT-IR spectra were recorder with a
Perkin-Elmer Spectrum BX spectrometer. High-resolution mass spectra
were measured with a Perkin-Elmer Finnigan MAT 95 S spectrometer.
Optical rotations were measured by using a Perkin-Elmer 241 polari-
meter at room temperature in a 1 dm cell at the sodium D radiation
(λ 589 nm) and are reported as follows: [R]Drt (c in g/100 mL, solvent).
HPLC analyses were performed on a Thermo Separation Product Pump
P100 instrument with a UV detector and a chiral stationary-phase
column (Chiralpak OJ-H or AD).
Synthesis of N-[(Pyridin-2-yl)(ferrocenyl)methyl]-N-[(10R)-
10-phenylethyl]amine (L10). A solution of ferrocenecarboxalde-
hyde (500 mg, 2.34 mmol) and (R)-1-phenylethylamine (283 mg, 2.34
mmol) in dry THF (10 mL) was stirred at room temperature over
anhydrous MgSO4 for 24 h. The reaction mixture was filtered through a
pad of Celite and washed with DCM, and the solvents were removed
under vacuum to yield the corresponding imine (100%, 743 mg).
To a stirred solution of the crude imine (250 mg, 0.79 mmol) and
2-bromopyridine (162 mg, 1.03 mmol) in dry THF (7 mL) at ꢀ78 °C
was added dropwise n-BuLi (0.67 mL, 1.06 mmol, 1.6 M solution in
hexane). The mixture was stirred for 5 min at ꢀ78 °C and then for 20 h
at room temperature. The reaction was quenched by adding a saturated
solution of NH4Cl. The aqueous layer was extracted with CH2Cl2, and
the combined organic layers were dried over MgSO4, filtered, and
concentrated under vacuum. The crude product was purified by flash
chromatography on silica gel, using petroleum ether/ethyl acetate (85/15)
as eluent, to afford one of the desired diastereomers (33%, 104 mg).
The first diastereomer eluted, L10a, was isolated as an orange oil (104
mg). [R]D20 = +56.2° (c 0.376, CHCl3). 1H NMR (CDCl3, 300 MHz):
δ 8.53 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H, Ar), 7.57 (td, J = 7.6, 1.8 Hz, 1H,
Ar), 7.33ꢀ7.15 (m, 6H), 7.09 (ddd, J = 7.4, 4.9, 1.2 Hz, 1H, Ar), 4.28 (s,
1H, CHꢀN), 4.10ꢀ4.04 (m, 2H, Cp), 4.00ꢀ3.94 (m, 2H, Cp), 3.84 (s,
5H, Cp), 3.41 (q, J=6.6 Hz, 1H, CHꢀN), 2.29(brs, 1H, NH),1.25(d, J=
6.6 Hz, 3H, Me). 1H NMR ([D6]DMSO, 300 MHz) δ 8.52 (ddd, J = 4.8,
1.7, 0.8 Hz, 1H, Ar), 7.77 (td, J = 7.6, 1.8 Hz, 1H, Ar), 7.48 (d, J = 7.8 Hz,
1H, Ar), 7.39ꢀ7.20 (m, 6H, Ar), 4.25 (d, J = 7.5 Hz, 1H, CHꢀN), 4.10
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purified by flash chromatography on silica gel, using petroleum ether/
ethyl acetate (90/10) as eluent, to afford an inseparable mixture of the
two desired diastereomers (dr = 51/49, 95%, 397 mg) as a yellow solid.
1H NMR (CDCl3, 300 MHz): δ 8.54ꢀ8.47 (m, 2H, Ar 2 dia (dia =
diastereomer)), 7.86ꢀ7.61 (m, 8H, Ar 2 dia, 7.52ꢀ6.91 (m, 22H, Ar 2
dia, 4.77 (s, 1H, CHꢀN 1 dia, 4.74 (s, 1H, CHꢀN 1 dia), 4.47 (q, J = 6.6
Hz, 1H, CHꢀN 1 dia), 4.43 (q, J = 6.7 Hz, 1H, CHꢀN 1 dia), 2.88 (br s,
2H, NH 2 dia), 1.43 (d, J = 6.6 Hz, 3H, Me 1 dia), 1.43 (d, J = 6.7 Hz, 3H,
Me 1 dia). 1H NMR ([D6]DMSO, 200 MHz) δ 8.46 (t, J = 4.4 Hz, 2H,
Ar 2 dia), 7.99ꢀ7.59 (m, 10H, Ar 2 dia), 7.58ꢀ7.02 (m, 20H, Ar 2 dia),
4.76 (s, 2H, CHꢀN 2 dia), 4.54ꢀ4.27 (m, 2H, CHꢀN 2 dia), 3.46 (br s,
2H, NH 2 dia), 1.42 (d, J = 6.5 Hz, 6H, Me 2 dia). 13C NMR (CDCl3, 75
MHz): δ 162.65 (Cquat, Ar), 162.29 (Cquat, Ar), 149.61 (Ar), 149.08
(Ar), 143.25 (Cquat, Ar), 142.96 (Cquat, Ar), 141.25 (Cquat, Ar), 141.17
(Cquat, Ar), 136.35 (Ar), 136.34 (Ar), 134.01 (Cquat, Ar), 133.97(Cquat, Ar),
131.47 (Cquat, Ar), 131.46 (Cquat, Ar), 128.88 (Ar), 128.82 (Ar), 128.50
(Ar), 128.48 (Ar), 128.16 (Ar), 127.62 (Ar), 127.26 (Ar), 127.12 (Ar),
127.07 (Ar), 125.85 (Ar), 125.82 (Ar), 125.56 (Ar), 125.26 (Ar), 123.44
(Ar), 123.10 (Ar), 123.02 (Ar), 122.96 (Ar), 122.29 (Ar), 121.97 (Ar),
121.81 (Ar), 65.10 (CHꢀN), 64.87 (CHꢀN), 51.31 (CHꢀN), 50.26
(CHꢀN), 24.48 (Me), 23.81(Me). HRMS (ESI): calcd for C24H23N2
(MH+) 339.1861, found 339.1848.
Synthesis of (2S)-2-Phenyl-2-(phenyl(pyridin-2-yl)methyl-
amino)ethanol ((1S,10S)-L14). A solution of pyridine-2-carboxalde-
hyde (300 mg, 2.80 mmol) and (S)-2-phenylglycinol (384 mg, 2.80
mmol) in dry THF (14 mL) was stirred at room temperature over
anhydrous MgSO4 for 24 h. The reaction mixture was filtered through a
pad of Celite and washed with DCM, and the solvents were removed
under vacuum to yield the corresponding imine (100%, 632 mg).
To a stirred solution of the crude imine (300 mg, 1.33 mmol) in dry
THF (15 mL) at ꢀ78 °C was added dropwise PhLi (2.28 mL, 4.11
mmol, 1.8 M solution in dibutyl ether). The mixture was stirred at room
temperature for 20 h, and the reaction was quenched by adding a
saturated solution of NH4Cl. The aqueous layer was extracted with
CH2Cl2, and the combined organic layers were dried over MgSO4,
filtered, and concentrated under vacuum. The crude product was
purified by flash chromatography on silica gel, using dichloro-
methane/methanol (98/2) as eluent, to afford an inseparable mixture
(dr = 92/8) of the two desired diastereomers (68%, 274 mg) as an
orange oil. 1H NMR (CDCl3, 300 MHz): δ 8.61 (ddd, J = 4.9, 1.8, 0.9
Hz, 1H, Ar major), 7.55 (td, J = 7.7, 1.8 Hz, 1H, Ar major), 7.4ꢀ7.29 (m,
10H, Ar major), 7.15 (ddd, J = 7.5, 4.9, 0.8 Hz, 1H, Ar major), 7.02 (d, J =
7.9 Hz, 1H, Ar major), 4.95 (s, 1H, CHꢀN minor), 4.84 (s, 1H, CHꢀN
major), 3.88ꢀ3.62 (m, 3H, CHꢀN and CH2ꢀO major), 3.12 (br s, 2H,
NH and OH major). 1H NMR ([D6]DMSO, 300 MHz): δ 8.47 (ddd, J
= 4.8, 1.7, 0.8 Hz, 1H, Ar major), 7.65 (td, J = 7.7, 1.8 Hz, 1H, Ar major),
7.38ꢀ7.14 (m, 12H, Ar major), 4.99 (t, J = 5.4 Hz, 1H, OH major), 4.65
(s, 1H, CHꢀN major), 3.61 (br s, 1H, NH major), 3.58ꢀ3.38 (m, 3H,
CHꢀN and CH2ꢀO major). 13C NMR (CDCl3, 75 MHz): δ 161.94
(Cquat, Ar), 148.83 (Ar), 142.05 (Cquat, Ar), 140.38 (Cquat, Ar), 136.44
(Ar), 128.75 (2C, Ar), 128.70 (2C, Ar), 128.46 (2C, Ar), 127.64 (Ar),
127.61 (Ar), 127.47 (2C, Ar), 122.27 (Ar), 121.94 (Ar), 67.07
(CH2ꢀO), 64.25 (CHꢀN), 61.42 (CHꢀN). HRMS (ESI): calcd for
C20H21N2O (MH+) 305.1654, found 316.1636.
The mixture was stirred for 5 min at ꢀ78 °C and then 20 h at room
temperature. The reaction was quenched by adding a saturated solu-
tion of NH4Cl. The aqueous layer was extracted with CH2Cl2, and
the combined organic layers were dried over MgSO4, filtered, and
concentrated under vacuum. The crude product was purified by flash
chromatography on silica gel, using dichloromethane/methanol (98/2)
as eluent, to afford selectively one of the desired diastereomers (65%,
262 mg) as an orange oil. 1H NMR (CDCl3, 300 MHz): δ 8.65 (ddd, J =
4.9, 1.8, 0.9 Hz, 1H, Ar), 7.68 (td, J = 7.7, 1.8 Hz, 1H, Ar), 7.46ꢀ7.15 (m,
12H, Ar), 4.95 (s, 1H, CHꢀN), 3.88ꢀ3.61 (m, 3H, CHꢀN and
1
CH2ꢀO), 3.07 (br s, 2H, NH and OH). H NMR ([D6]DMSO, 300
MHz): δ 8.51 (ddd, J = 4.8, 1.7, 0.7 Hz, 1H, Ar), 7.76 (td, J = 7.6, 1.8 Hz,
1H, Ar), 7.43 (d, J = 7.8 Hz, 1H, Ar), 7.36ꢀ7.11 (m, 11H, Ar), 4.91 (t, J =
5.5 Hz, 1H, OH), 4.63 (s, 1H, CHꢀN), 3.50 (q, J = 5.7 Hz, 1H,
CHꢀN), 3.46 (br s, 1H, NH), 3.43 (dd, J = 8.4, 3.0 Hz, 2H, CH2ꢀO).
13C NMR (CDCl3, 75 MHz): δ 161.99 (Cquat, Ar), 149.45 (Ar), 143.01
(Cquat, Ar), 140.74 (Cquat, Ar), 136.77 (Ar), 128.67 (2C, Ar), 128.61
(2C, Ar), 127.64 (Ar), 127.57 (2C, Ar), 127.48 (2C, Ar), 127.35 (Ar),
122.87 (Ar), 122.24 (Ar), 67.15 (CH2ꢀO), 64.94 (CHꢀN), 62.45
(CHꢀN). HRMS (ESI): calcd for C20H21N2O (MH+) 305.1654, found
316.1660.
General Procedure for the Synthesis of the Palladium
Complexes C1ꢀC14. To a stirred solution of ligand (1 equiv) in
freshly distilled MeOH (10 mL for 0.5 mmol of ligand) was added
Na2PdCl4 (1 equiv). The mixture was stirred at room temperature for 16
h, and the solvent was removed by evaporation under vacuum. The
residue was then filtered through a pad of silica gel (first with EtOAc/
petroleum ether (4/6) as eluent to remove traces of ligand and then with
EtOAc) to afford the corresponding palladium complex.
Complex C1. The reaction was performed with 100 mg (0.61 mmol)
of L1 and 180 mg (0.61 mmol) of Na2PdCl4. The palladium complex
was obtained as a yellow powder (176 mg, 85%). 1H NMR
([D6]DMSO, 300 MHz): δ 8.73 (d, J = 5.4 Hz, 1H, Ar), 8.08 (t, J =
7.5 Hz, 1H, Ar), 7.66 (t, J = 7.7 Hz, 1H, Ar), 7.53 (t, J = 6.4 Hz, 1H, Ar),
6.10 (br s, 1H, NH), 4.50 (dd, J = 11.4, 5.4 Hz, 1H, CH2ꢀN), 3.99 (d, J =
16.5 Hz, 1H, CH2ꢀN), 2.75 (m, 1H, CH2ꢀN), 2.50 (m, 1H, CH2ꢀN),
0.88 (d, J = 4.6 Hz, 6H, 2 Me). 13C NMR ([D6]DMSO, 75 MHz): δ
164.42 (Cquat, Ar), 149.96 (C, Ar), 141.08 (C, Ar), 125.03 (C, Ar),
123.75 (C, Ar), 62.14 (CH2ꢀN), 59.87 (CH2ꢀN), 26.28 (CH), 21.80
(Me), 21.02 (Me). HRMS (ESI): calcd for C10H16N235Cl2104Pd (M +
Na) 362.9618, found 362.9616.
Complex C7. The reaction was performed with 100 mg (0.47 mmol)
of L7 and 139 mg (0.47 mmol) of Na2PdCl4. The palladium complex
(inseparable mixture of two diastereomers, dr = 50/50) was obtained as
a yellow powder (178 mg, 97%). 1H NMR ([D6]DMSO, 300 MHz): δ
8.57 (dd, J = 5.8, 0.9 Hz, 1H, Ar), 8.44 (dd, J = 5.8, 0.9 Hz, 1H, Ar),
7.99ꢀ7.80 (m, 2H, Ar), 7.70 (dd, J = 8.0, 1.4 Hz, 2H, Ar), 7.60 (dd, J =
8.0, 1.4 Hz, 2H, Ar), 7.45 (d, J = 8.0 Hz, 1H, Ar), 7.39ꢀ7.10 (m, 9H, Ar),
6.88 (br s, J = 2.5 Hz, 1H, NH), 6.81 (t, J = 5.0 Hz, 1H, NH), 4.50ꢀ4.34
(m, 2H, 1H CH2ꢀN and 1H CHꢀN), 4.34ꢀ4.18 (m, 2H, 1H CH2ꢀN
and 1H CHꢀN), 4.02 (d, J = 17.5 Hz, 1H, CH2ꢀN), 3.96 (d, J = 17.5 Hz,
1H, CH2ꢀN), 1.68 (d, J = 7.0 Hz, 3H, Me), 1.64 (d, J = 7.0 Hz, 3H, Me).
13C NMR ([D6]DMSO, 75 MHz): δ 164.36 (Cquat, Ar), 164.06 (Cquat
Ar), 148.42 (Ar), 148.34 (Ar), 139.53 (Ar), 139.38 (Ar), 138.16 (Cquat
,
,
Ar), 138.09 (Cquat, Ar), 128.85 (2C, Ar), 128.81 (2C, Ar), 128.22 (2C,
Ar), 128.18 (2C, Ar), 123.32 (Ar), 123.13 (Ar), 121.89 (Ar), 121.70
(Ar), 60.95 (CHꢀN), 60.01 (CHꢀN), 55.95 (CH2ꢀN), 54.30
(CH2ꢀN), 19.07 (Me), 18.57 (Me). HRMS (ESIꢀ, MeOH): calcd
for C14H16N235Cl3104Pd [M + Cl] 422.9412, found 422.9414.
Synthesis of (2S)-2-Phenyl-2-(phenyl(pyridin-2-yl)methyl-
amino)ethanol ((1R,10S)-L14). A solution of benzaldehyde (297
mg, 2.80 mmol) and (S)-2-phenylglycinol (384 mg, 2.80 mmol) in dry
THF (14 mL) was stirred at room temperature over anhydrous MgSO4
for 24 h. The reaction mixture was filtered through a pad of Celite and
washed with DCM, and the solvents were removed under vacuum to
yield the corresponding imine (100%, 629 mg).
To a stirred solution of the crude imine (300 mg, 1.33 mmol) and
2-bromopyridine (421 mg, 2.66 mmol) in dry THF (15 mL) at ꢀ78 °Cwas
added dropwise n-BuLi (1.83 mL, 2.93 mmol, 1.6 M solution in hexane).
Complex (1R,10R)-C8. The reaction was performed with 34 mg (0.15
mmol) of (1R,10R)-L8 and 44 mg (0.15 mmol) of Na2PdCl4. The
palladium complex was obtained as a yellow powder (57 mg, 95%).
1H NMR ([D6]DMSO, 300 MHz): δ 8.46 (dd, J = 5.8, 0.9 Hz, 1H, Ar),
7.92 (td, J = 7.7, 1.5 Hz, 1H, Ar), 7.61 (dd, J = 7.8, 1.6 Hz, 2H, Ar), 7.41
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(d, J = 7.4 Hz, 1H, Ar), 7.33 (ddd, J = 7.4, 5.8, 1.4 Hz, 1H, Ar), 7.27ꢀ7.14
(m, 3H, Ar), 6.41 (d, J = 6.3 Hz, 1H, NH), 4.32ꢀ4.10 (m, 2H, 2
CHꢀN), 1.80 (d, J = 6.7 Hz, 3H, Me), 1.73 (d, J = 7.0 Hz, 3H, Me). 13C
NMR ([D6]DMSO, 75 MHz): δ 167.55 (Cquat, Ar), 148.81 (Ar), 139.90
(Ar), 138.96 (Cquat, Ar), 128.51 (2C, Ar), 128.26 (2C, Ar), 128.11 (Ar),
123.45 (Ar), 121.84 (Ar), 61.29 (CHꢀN), 61.19 (CHꢀN), 23.28 (Me),
20.14 (Me). HRMS (ESIꢀ, MeOH): calcd for C15H18N235Cl3104Pd
[M + Cl] 436.9569, found 436.9570.
δ 8.43 (d, J = 7.2 Hz, 2H, Ar major), 7.98 (d, J = 7.0 Hz, 2H, Ar minor),
7.87ꢀ7.75 (m, 3H, Ar major and minor), 7.63ꢀ7.42 (m, 9H, Ar major
and minor), 7.33ꢀ7.00 (m, 9H, Ar major and minor), 6.92 (d, J = 7.3 Hz,
1H, Ar major), 6.24 (s, 1H, NH major), 6.11 (d, J = 7.2 Hz, 1H, NH
minor), 5.57 (s, 1H, CHꢀN major), 5.19 (s, 1H, CHꢀN minor), 4.06
(p, J = 6.6 Hz, 1H, CHꢀN minor), 3.94ꢀ3.79 (m, 1H, CHꢀN major),
2.71 (s, 3H, Me minor), 2.57 (s, 3H, Me major), 1.83 (d, J = 6.9 Hz, 3H,
Me minor), 1.68 (d, J = 6.7 Hz, 3H, Me major). 13C NMR ([D6]DMSO,
75 MHz): δ 164.59 (Cquat, Ar), 163.89 (Cquat, Ar), 162.41 (Cquat, Ar),
161.53 (Cquat, Ar), 140.19 (Ar), 139.64 (Cquat, Ar), 139.58 (Ar), 139.52
(Cquat, Ar), 138.68 (Cquat, Ar), 138.18 (Cquat, Ar), 130.12, 129.89,
129.43, 129.32, 129.18, 129.01, 128.80 (Ar), 128.53, 128.26, 125.96
(Ar), 125.22 (Ar), 121.27 (Ar), 120.47 (Ar), 75.96 (CHꢀN), 70.41
(CHꢀN), 64.91 (CHꢀN), 62.43 (CHꢀN), 26.83 (Me), 26.65 (Me),
21.63 (Me), 20.77 (Me). HRMS (ESI+, CH3CN): calcd for
C23H25N335Cl104Pd (M + CH3CN ꢀ Cl) 484.0772, found 484.0764.
Complexes C13a,b. The reaction was performed on 117 mg
(0.35 mmol) of L13 (mixture of two diastereomers) and 102 mg (0.35
mmol) of Na2PdCl4. The two desired diastereomers (dr = 51/49) were
obtained in 92% overall yield and were separated by flash chromatography
on silica gel, using petroleum ether/ethyl acetate (90/10) as eluent.
The first eluted diastereomer C13a was isolated as a yellow powder
(81 mg). 1H NMR ([D6]DMSO, 300 MHz): δ 8.89 (d, J = 7.9 Hz, 1H,
Ar), 8.21 (d, J = 5.5 Hz, 1H, Ar), 8.02 (d, J = 7.2 Hz, 1H, Ar), 7.95ꢀ7.82
(m, 3H, Ar), 7.81ꢀ7.66 (m, 2H, Ar), 7.64ꢀ7.30 (m, 6H, Ar), 7.25ꢀ7.09
(m, 2H, Ar), 6.58 (s, 1H, NH), 5.34 (s, 1H, CHꢀN), 5.30ꢀ5.18 (m, 1H,
CHꢀN), 1.98 (d, J = 6.7 Hz, 3H, Me). 13C NMR ([D6]DMSO, 75
Complex (1S,10R)-C8. The reaction was performed on 36 mg
(0.16 mmol) of (1S,10R)-L8 and 47 mg (0.16 mmol) of Na2PdCl4.
The palladium complex was obtained as a yellow powder (56 mg, 93%).
1H NMR ([D6]DMSO, 300 MHz): δ 8.32 (d, J = 5.7 Hz, 1H, Ar),
7.86ꢀ7.62 (m, 3H, Ar), 7.29ꢀ6.91 (m, 5H, Ar), 6.36 (br s, 1H, NH),
4.28 (q, J = 6.5 Hz, 1H, CNꢀN), 3.87 (qd, J = 6.5, 2.1 Hz, 1H, CHꢀN),
1.83 (d, J = 6.7 Hz, 3H, Me), 1.66 (d, J = 6.9 Hz, 3H, Me). 13C NMR
([D6]DMSO, 75 MHz): δ 167.79 (Cquat, Ar), 148.35 (Ar), 139.47 (Ar),
138.51 (Cquat, Ar), 129.30 (2C, Ar), 128.04 (Ar), 127.80 (2C, Ar),
123.03 (Ar), 121.39 (Ar), 66.04 (CHꢀN), 63.54 (CHꢀN), 23.31 (Me),
21.34 (Me). HRMS (ESIꢀ, MeOH): calcd for C15H18N235Cl3104Pd
[M + Cl] 436.9569, found 436.9570.
Complex (1R,10R)-C9. The reaction was performed on 100 mg
(0.35 mmol) of (1R,10R)-L9 and 102 mg (0.35 mmol) of Na2PdCl4.
The palladium complex was obtained as a yellow powder (157 mg, 97%).
1H NMR ([D6]DMSO, 300 MHz): δ 8.47 (d, J = 5.2 Hz, 1H, Ar), 7.86
(d, J = 6.8 Hz, 5H, Ar), 7.57ꢀ7.36 (m, 4H, Ar), 7.30 (t, J = 6.7 Hz, 1H,
Ar), 7.26ꢀ7.13 (m, 3H, Ar), 6.65 (d, J = 4.8 Hz, 1H, NH), 5.47 (s, 1H,
CHꢀN), 4.68ꢀ4.39 (m, 1H, CHꢀN), 1.82 (d, J = 6.9 Hz, 3H, Me). 13C
NMR ([D6]DMSO, 75 MHz): δ 165.83 (Cquat, Ar), 148.41 (Ar), 139.93
(Ar), 138.75 (Cquat, Ar), 137.57 (Cquat, Ar), 129.10 (2C, Ar), 128.92
(Ar), 128.88 (2C, Ar), 128.64 (2C, Ar), 128.29 (Ar), 128.20 (2C, Ar),
123.56 (Ar), 123.00 (Ar), 67.93 (CHꢀN), 61.83 (CHꢀN), 18.75 (Me).
HRMS (ESIꢀ, MeOH): calcd for C20H19N235Cl2104Pd (M ꢀ H)
460.9966, found 460.9965.
MHz): δ 164.60 (Cquat, Ar), 148.33 (Ar), 139.73 (Ar), 137.18 (Cquat
,
Ar), 134.35 (Cquat, Ar), 133.17 (Cquat, Ar), 130.88 (Cquat, Ar), 128.97,
128.87, 128.83, 128.51, 126.70, 126.00, 125.80, 125.05, 123.85, 123.52,
122.94, 68.96 (CHꢀN), 56.26 (CHꢀN), 21.10 (Me). HRMS (ESI+,
CH3CN): calcd for C26H25N335Cl104Pd (M + CH3CN ꢀ Cl):
520.0772, found 520.0751.
Complex (1S,10R)-C9.The reaction was performed on 50 mg (0.17 mmol)
of (1S,10R)-L9 and 51 mg (0.17 mmol) of Na2PdCl4. The palladium complex
was obtained as a yellow powder (72 mg, 91%). 1H NMR ([D6]DMSO, 300
MHz): δ8.42 (d, J=4.9Hz, 1H, Ar), 8.09(d, J=7.0 Hz, 2H, Ar), 7.94(d, J=
6.7 Hz, 2H, Ar), 7.71 (td, J = 7.7, 1.4 Hz, 1H, Ar), 7.54ꢀ7.37 (m, 3H, Ar),
7.28ꢀ7.04 (m, 5H, Ar), 6.55 (br s, 1H, NH), 5.44 (s, 1H, CHꢀN),
4.16ꢀ4.05 (m, 1H, CHꢀN), 1.74 (d, J = 6.8 Hz, 3H, Me). 13C NMR
([D6]DMSO, 75 MHz): δ 165.68 (Cquat, Ar), 148.23 (Ar), 139.76 (Ar),
138.44 (Cquat, Ar), 137.79 (Cquat, Ar), 129.57 (2C, Ar), 128.96 (Ar), 128.85
(2C, Ar), 128.53 (2C, Ar), 128.29 (Ar), 127.94 (2C, Ar), 123.38 (Ar), 122.69
(Ar), 73.53 (CHꢀN), 64.75 (CHꢀN), 21.39 (Me). HRMS (ESIꢀ,
MeOH): calcd for C20H19N235Cl2104Pd (M ꢀ H) 460.9966, found
460.9968.
The second diastereomer C13b was isolated as a yellow powder (85 mg).
1H NMR ([D6]DMSO, 300 MHz): δ 8.61ꢀ8.50 (m, 2H, Ar), 8.47 (d,
J = 7.2 Hz, 1H, Ar), 7.95ꢀ7.83 (m, 2H, Ar), 7.72 (t, J = 7.7 Hz, 1H, Ar),
7.64ꢀ7.45 (m, 3H, Ar), 7.39ꢀ7.24 (m, 6H, Ar), 7.20 (d, J = 7.8 Hz, 1H,
Ar), 5.64 (s, 1H, NH), 5.46ꢀ5.30 (m, 1H, CHꢀN), 5.38 (s, 1H,
CHꢀN), 1.92 (d, J = 6.7 Hz, 3H, Me). 13C NMR ([D6]DMSO, 75
MHz) δ 164.87 (Cquat, Ar), 148.23 (Ar), 139.73 (Ar), 137.66 (Cquat
,
Ar), 133.54 (Cquat, Ar), 133.24 (Cquat, Ar), 130.73 (Cquat, Ar), 129.44
(Ar), 129.11 (Ar), 129.00 (3C, Ar), 127.83 (2C, Ar), 127.09 (Ar),
126.99 (Ar), 125.91 (Ar), 125.05 (Ar), 124.04 (Ar), 122.72 (Ar), 122.24
(Ar), 70.52 (CHꢀN), 57.44 (CHꢀN), 19.31 (Me). HRMS (ESI+,
CH3CN): calcd for C26H25N335Cl104Pd (M + CH3CN ꢀ Cl) 520.0772,
found 520.0752.
Complex C10a. The reaction was performed on 30 mg (0.076 mmol)
of L10a and 22 mg (0.076 mmol) of Na2PdCl4. The palladium complex
was obtained as an orange powder (43 mg, 98%). 1H NMR
([D6]DMSO, 300 MHz): δ 8.51 (d, J = 5.5 Hz, 1H, Ar), 8.03 (t, J =
7.2 Hz, 1H, Ar), 7.69 (d, J = 7.3 Hz, 3H, Ar), 7.43 (t, J = 6.3 Hz, 1H, Ar),
7.36ꢀ7.21 (m, 3H, Ar), 5.39 (d, J = 6.8 Hz, 1H, NH), 5.03 (s, 1H, Cp),
4.91 (s, 1H, CHꢀN), 4.39 (s, 1H, Cp), 4.35 (s, 2H, Cp), 4.30ꢀ4.16 (m,
1H, CHꢀN), 1.90 (d, J = 6.9 Hz, 3H, Me). 13C NMR ([D6]DMSO, 75
Complex (1S,10S)-C14. The reaction was performed on 51 mg
(0.17 mmol) of (1S,10S)-L14 and 50 mg (0.17 mmol) of Na2PdCl4.
The palladium complex was obtained as a yellow powder (75 mg, 94%).
1H NMR ([D6]DMSO, 300 MHz): δ 8.42 (d, J = 5.3 Hz, 1H, Ar minor),
8.28 (d, J = 5.4 Hz, 1H, Ar major), 8.09ꢀ7.88 (m, 4H, Ar major),
7.86ꢀ7.71 (m, 1H, Ar major), 7.65ꢀ7.42 (m, 3H, Ar major), 7.36 (d, J =
7.6 Hz, 1H, Ar major), 7.27ꢀ7.09 (m, 4H, Ar major), 5.97 (s, 1H, NH
major), 5.76 (s, 1H, CHꢀN minor), 5.66 (s, 1H, CHꢀN major), 5.13 (t,
J = 4.7 Hz, 1H, OH major), 4.42ꢀ4.25 (m, 1H, CH2ꢀO), 4.04 (t, J = 6.7
Hz, 1H, CHꢀN major), 3.92ꢀ3.79 (m, 1H, CH2ꢀO major). 13C NMR
([D6]DMSO, 75 MHz): δ 164.74 (Cquat, Ar), 148.34 (Ar), 139.80 (Ar),
137.79 (Cquat, Ar), 135.85 (Cquat, Ar), 130.10 (2C, Ar), 129.22 (3C, Ar),
128.52 (Ar), 128.15 (2C, Ar), 127.92 (2C, Ar), 123.55 (Ar), 122.78
(Ar), 74.58 (CHꢀN), 71.42 (CHꢀN), 61.77 (CH2ꢀO). HRMS
(ESIꢀ, MeOH): calcd for C20H19N2O35Cl2104Pd (M ꢀ H) 476.9915,
found 476.9902.
MHz): δ 164.39 (Cquat, Ar), 148.74 (Ar), 139.91 (Ar), 138.78 (Cquat
,
Ar), 128.60 (2C, Ar), 128.51 (Ar), 128.44 (2C, Ar), 124.02 (Ar), 123.62
(Ar), 87.25 (Cquat, Cp), 68.92 (5C, Cp), 68.48 (2C, Cp), 68.10 (Cp),
67.45 (Cp), 65.26 (CHꢀN), 61.91 (CHꢀN), 21.19 (Me). HRMS
(ESIꢀ, MeOH): calcd for C24H24N235Cl356Fe104Pd [M + Cl]
606.9394, found 606.9389.
Complex C12. The reaction was performed on 60 mg (0.20 mmol) of
L12 (mixture of two diastereomers) and 59 mg (0.20 mmol) of
Na2PdCl4. The two desired diastereomers were obtained as a yellow
powder (dr = 55/45, 88 mg, 93%). 1H NMR ([D6]DMSO, 300 MHz):
Complex (1R,10S)-C14. The reaction was performed on 57 mg
(0.19 mmol) of (1R,10S)-L14 and 55 mg (0.19 mmol) of Na2PdCl4.
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ARTICLE
The palladium complex was obtained as a yellow powder (89 mg, 99%).
1H NMR ([D6]DMSO, 300 MHz): δ 8.42 (dd, J = 5.8, 0.9 Hz, 1H, Ar),
7.90 (d, J = 7.5 Hz, 2H, Ar), 7.84 (td, J = 7.8, 1.5 Hz, 1H, Ar), 7.76 (d, J =
7.0 Hz, 2H, Ar), 7.59ꢀ7.43 (m, 3H, Ar), 7.35 (d, J = 7.8 Hz, 1H, Ar),
7.28 (ddd, J = 7.3, 6.0, 1.3 Hz, 1H, Ar), 7.25ꢀ7.12 (m, 3H, Ar), 5.77 (s,
1H, CHꢀN), 5.57 (t, J = 4.7 Hz, 1H, OH), 5.44 (d, J = 2.4 Hz, 1H, NH),
4.65ꢀ4.42 (m, 2H, CH2ꢀO and CHꢀN), 3.80 (dt, J = 10.3, 4.3 Hz, 1H,
CH2ꢀO). 13C NMR ([D6]DMSO, 75 MHz): δ 165.26 (Cquat, Ar),
148.29 (Ar), 139.90 (Ar), 137.97 (Cquat, Ar), 133.96 (Cquat, Ar), 130.18
(2C, Ar), 129.34 (2C, Ar), 129.29 (Ar), 128.83 (Ar), 128.21 (2C, Ar),
128.14 (2C, Ar), 123.70 (Ar), 123.06 (Ar), 67.31, 66.76, 58.37. HRMS
(ESIꢀ, MeOH): calcd for C20H19N2O35Cl2104Pd (M ꢀ H) 476.9915,
found 476.9914.
General Procedure for the SuzukiꢀMiyaura Coupling
Reaction. To a stirred suspension of 1-bromo-2-methoxynaphthalene
(54 mg, 0.226 mmol, 1 equiv), naphthalen-1-ylboronic acid (78 mg,
0.452 mmol, 2 equiv), and Cs2CO3 (294 mg, 0.904 mmol, 4 equiv) in a
degassed mixture of toluene (1 mL), absolute ethanol (1 mL), and water
(0.5 mL) was added the palladium complex (5 mol %). The mixture was
stirred at 80 °C for 24 h under argon. Water was then added, and the
aqueous phase was extracted with dichloromethane. The combined
organic layers were dried (MgSO4), filtered, and concentrated under
vacuum. The crude product was purified by flash chromatography on
silica gel (petroleum ether/EtOAc 98/2) to give the desired binaphthyl
compound 17. 1H NMR (CDCl3, 300 MHz): δ 7.96 (t, J = 8.4 Hz, 2H),
7.95 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 6.3 Hz, 1H), 7.65ꢀ7.60 (m, 3H),
7.37ꢀ7.15 (m, 5H), 3.77 (s, 3H). HPLC (Chiralpak OJ-H, hexane/2-
propanol 95/5, 1.0 mL/min, λ 254 nm): tR = 12.75 min (major) and
23.70 min (minor), ee = 40% in favor of the S enantiomer.27
General Procedure for Oxidative Naphthol Coupling. To a
solution of 3-hydroxynaphth-2-yl carboxylic acid methyl ester (50.5 mg,
0.25 mmol) dissolved in DCE was added CuI (4.8 mg, 0.1 equiv) and
L10 (9.9 mg, 0.1 equiv) to yield a greenish solution which was actively
purged with air for 1 min and then placed under an air atmosphere at
40 °C. After 48 h, the reaction mixture was diluted with CH2Cl2 and was
washed with 1 N HCl. The aqueous phase was back-extracted with
CH2Cl2, and the combined organic solutions were dried over Na2SO4.
Filtration and concentration afforded the crude product, which was purified
by flash chromatography on silica gel (petroleum ether/EtOAc 98/2)
to give the desired binaphthyl compound 21. 1HNMR(CDCl3, 300 MHz):
δ 10.76 (s, 2H), 8.71 (s, 2H), 7.95ꢀ7.92 (m, 2H), 7.39ꢀ7.16 (m, 6H),
4.06 (s, 3H). HPLC (Chiralpak AD, hexane/2-propanol 90/10, 1.0 mL/
min, λ 254 nm): tR = 13.98 min (major) and 25.23 min (minor),
ee = 61% in favor of the S enantiomer.28
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’ ASSOCIATED CONTENT
S
Supporting Information. Text, tables, figures, and CIF
b
files giving 1H and 13C NMR data for ligands and complexes as
well as crystallographic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
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’ AUTHOR INFORMATION
Espinet, P. Chem. Eur. J. 2006, 12, 9346–9352. (g) Kasꢀak, P.; Mereiter,
K.; Widhalm, M. Tetrahedron: Asymmetry 2005, 16, 3416–3426.
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A.; Marinetti, A.; Baudoin, O.; Guꢀenard, D.; Guꢀeritte, F. J. Org. Chem.
2003, 68, 4897–4905. (j) Mikami, K.; Miyamoto, T.; Hatano, M. Chem.
Commun. 2004, 2082–2083. (k) Cammidge, A. N.; Crꢀepy, K. V. L.
Tetrahedron 2004, 60, 4377–4386. (l) Cammidge, A. N.; Crꢀepy, K. V. L.
Chem. Commun. 2000, 1723–1724. (m) Willis, M. C.; Powell, L. H. W.;
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(n) Jensen, J. F.; Johannsen, M. Org. Lett. 2003, 5, 3025–3028.
(o) Castanet, A.-S.; Colobert, F.; Broutin, P.-E.; Obringer, M. Tetra-
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Corresponding Author
*Fax: +33 1 3925 4452. E-mail: prim@chimie.uvsq.fr.
’ ACKNOWLEDGMENT
We thank the MENR, CNRS, UVSQ, UPSud-11, PRES
Universud Paris, CICYT (Project CTQ2010-16237), General-
itat de Catalunya (2009/SGR/00279), and ENSCCF for finan-
cial support.
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Organometallics
ARTICLE
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