Synthesis and crystallographic characterization of chiral bis-oxazoline-amides. Fine-tunable ligands for Pd-catalyzed asymmetric alkylations

Article abstract of DOI:10.1021/jo060767v

New chiral chelating C₂ bis-oxazoline-amide ligands (1) exhibiting a highly flexible molecular structure have been prepared in high yield through a versatile synthetic pathway. Combined crystallographic, variable temperature (VT)-NMR, IR, and ESI-MS studies have been carried out to investigate the nature of the 1-Pd complexes that are effective tools in controlling the stereochemical outcome of Pd-catalyzed allylic alkylations (ee up to 98%).

Full text of DOI:10.1021/jo060767v

Synthesis and Crystallographic Characterization of Chiral
Bis-oxazoline-amides. Fine-Tunable Ligands for Pd-Catalyzed
Asymmetric Alkylations
Vincenzo Giulio Albano, Marco Bandini, Magda Monari,*,† Eleonora Marcucci,
Fabio Piccinelli, and Achille Umani-Ronchi*,†
Dipartimento di Chimica “G. Ciamician”, UniVersita` di Bologna. Via Selmi, 2 40126 Bologna, Italy
achille.umanironchi@unibo.it; magda.monari@unibo.it
ReceiVed April 12, 2006
New chiral chelating C2 bis-oxazoline-amide ligands (1) exhibiting a highly flexible molecular structure
have been prepared in high yield through a versatile synthetic pathway. Combined crystallographic, variable
temperature (VT)-NMR, IR, and ESI-MS studies have been carried out to investigate the nature of the
1-Pd complexes that are effective tools in controlling the stereochemical outcome of Pd-catalyzed allylic
alkylations (ee up to 98%).
Introduction
to properly choose the appropriate inorganic counterpart (cata-
laphoric unit). Fine-tuning the catalytic properties of chiral
ligands, by varying their electronic and steric features, is of
major interest for the development of new classes of chiral
catalysts of wide interest. This target is pursued often by
condensing molecular frameworks present in different “privi-
leged ligands” to create new effective asymmetric environ-
ments.3
Design and synthesis of chiral ligands represent central issues
for chemists working in a number of areas: catalysis, new
materials, and medicinal chemistry.1 In particular, the search
for innovative, effective, and low cost asymmetric organome-
tallic catalysts continues to gain interest for practical and
environmental reasons.2
During the development of new chiral metal-based catalytic
systems, the complementary organic and inorganic approaches
are crucial to design chiral ligand motifs (chiraphoric units) and
We have recently described a new class of C2-symmetric
diamino-oligothiophene ligands4 that exhibited high effective-
† Fax: Int. Code +39(51)2099456.
(3) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691-1693.
(4) (a) Albano, V. G.; Bandini, M.; Melucci, M.; Monari, M.; Piccinelli,
F.; Tommasi, S.; Umani-Ronchi, A. AdV. Synth. Catal. 2005, 347, 1507-
1512. (b) Albano, V. G.; Bandini, M.; Barbarella, G.; Melucci, M.; Monari,
M.; Piccinelli, F.; Tommasi, S.; Umani-Ronchi, A. Chem.s Eur. J. 2006,
12, 667-675.
(1) Elsevier, C. J.; Reedijk, J.; Walton, P. H.; Ward, M. D. J. Chem.
Soc., Dalton Trans. 2003, 1869-1880.
(2) (a) Ojima, I. Catalytic Asymmetric Synthesis, 2nd ed.; Wiley-VCH:
New York, 2000. (b) ComprehensiVe Asymmetric Catalysis; Jacobsen, N.
E., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, Germany, 1999.
10.1021/jo060767v CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/26/2006
J. Org. Chem. 2006, 71, 6451-6458
6451

Albano et al.
SCHEME 1. Two-Step Sequence for the Synthesis of
Tetra-amide Intermediates 6
FIGURE 1. Structural flexibility of bis-oxazoline-amides.
ness in promoting Pd-catalyzed asymmetric allylic alkylation
(AAA)5 allyl carbonates. In view of their potentialities, chiral
polyaza ligands have had a deep impact in the asymmetric
synthesis scenario: (i) large availability in enantiomerically pure
form, (ii) ready modulation of the coordinating nitrogen group,
(iii) high stability under oxidative conditions (advantage over
phosphines), and (iv) flexibility of the coordination chemistry
(no restriction to exclusive noble metals chemistry).6 In this
context, we have been attracted by a valuable class of potentially
bi-, tri-, and tetradentate C2-tetraza ligands, namely, bis-
oxazoline-amides (1a, 1a′, 1b′, Figure 1) that recently were
introduced by Pfaltz and co-workers as promoters of molyb-
denum-catalyzed AAA.7
reaction of 4 with 2 equiv of the desired â-amino alcohol 5
(toluene, reflux, 72 h) gives rise to the corresponding diols, 6,
as white solids with chemical purity >95% by HPLC/1H NMR
determinations (isolated yield in the range of 75-95%, Scheme
1). In the final ring-closing step, a number of conventional
synthetic protocols were tested, namely, TsCl/NaOH,8 Burgess
reagent,9 and sulfur tetrafluoride (DAST).10 However, complex
mixtures of unknown products always were obtained; this
highlighted the poor chemoselectivity of the transformations.
Luckily, excellent results in terms of isolated compounds were
recorded using the nucleophilic fluorinating agent Deoxo-Fluor
(bis-(2-methyoxyethyl)aminosulfur trifluoride) as the ring-
closing promoter. This reagent, which already was successfully
adopted by Wipf and co-workers to promote the direct cycliza-
tion of amino alcohols to oxazoline rings,11 is a common
fluorinating agent, which has a higher thermal stability than that
of DAST. It also can be utilized at more convenient temperatures
(usually 0 vs -78 °C for DAST). The accepted mechanistic
pathway for the cyclization step is depicted in Scheme 2.
The O-S intermediate, which is postulated to be formed
rapidly first, rearranges to give a C-F species that, by adding
a base, evolves to the desired oxazoline ring. The protocol
adopted offers the remarkable advantage to avoid flash chro-
matographic purifications of the final ligands 1 that are highly
acid-sensitive.
The potentialities of this family of compounds lay on their
molecular skeleton, which allows large chemical diversities to
be obtained by combining different chiral acyclic and cyclic
backbones, bridging units, and substituents in the dihydroxazole
rings.
To further exploit the properties of type-1 ligands, we first
reexamined their synthesis and found a three-step synthetic route
more convenient than that previously reported (yield: 5a, 15%;
5a′, 14%; 5b′, 9%).7 This strategy enabled us to obtain a wide
library of structural analogues of 1 in good yields. The modular
compounds then were tested in the Pd-catalyzed AAA processes
in the presence of hindered and unhindered allyl carbonates with
the isolation of the corresponding products in quantitative yields
and ee up to 98%. Finally, we investigated the coordination
chemistry of 1a′ in the Pd-allyl species through a combined
crystallographic, variable temperature (VT)-NMR, IR, and ESI-
MS study. Here, a C1-symmetrical 26d-type N,O-coordination
mode is proposed to be involved as the active complex during
the enantiodiscriminating step of the reaction.
Results and Discussion
Notably, the bis-oxazoline-amides have been isolated in high
chemical purity (>95%, HPLC) by consecutive washings of
the reaction crude product with appropriate solvents. Remark-
ably, 6a′ undergoes the double cyclization in 91% yield.
Moreover, the ring-closing procedure was tolerant to steric and
electronic constraints. In fact, tert-leucinol and phenylglycinol
derivatives (6b and 6c′, respectively) smoothly cyclized under
optimal conditions affording the corresponding ligands in
reasonable yields (65-71%). The final purification by flash
chromatography was necessary only for 1c and the isolated yield
Synthesis of the Ligands. After several attempts, we have
found optimal reaction conditions for the synthesis of bis-
oxazolines anchored to 1,2-cyclohexane diamine backbones (1,
Schemes 1 and 2).
The three-step procedure involves the initial condensation
under basic conditions (triethylamine, TEA) of the enantio-
merically pure 1,2-cyclohexane diamine (2/2′) with ethyl
chlorooxocetate (3) in DCM that provides the bis-amide 4 in
89% yield without time-consuming purification steps. The
(5) (a) Trost, B. M.; Van Vraken, D. L. Chem. ReV. 1996, 96, 395-422.
(b) Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1-14. (c) Trost, B. M.;
Crawley, M. L. Chem. ReV. 2003, 103, 2921-2943. (d) Pfaltz, A.; Drudy,
J. D., III Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5723-5726.
(6) For a recent review on chiral tetraza ligands see: Fonseca, M. H.;
Konig, B. AdV. Synth. Catal. 2003, 345, 1173-1185.
(8) Bonini, F. S.; Giordano, M.; Fochi, M.; Comes-Franchini, M.;
Bernardi, L.; Capito`, E.; Ricci, A. Tetrahedron: Asymmetry 2004, 15,
1043-1051.
(9) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 907-910.
(10) Harm, A. M.; Knight, J. G.; Stemp, G. Synlett. 1996, 677-678.
(11) Philips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R. Org.
Lett. 2000, 2, 1165-1168.
(7) (a) Glorius, F.; Pfaltz, A. Org. Lett. 1999, 1, 141-144. (b) Glorius,
F.; Neuburger, M.; Pfaltz, A. HelV. Chim. Acta 2001, 84, 3178-3196.
6452 J. Org. Chem., Vol. 71, No. 17, 2006

Characterization of Chiral Bis-oxazoline-amides
SCHEME 2. Reaction Mechanism for the Deoxo-Fluor
Promoted Bis-oxazoline Ring Formation
as the achiral backbone (Scheme 4), which yielded 43% and
17%, respectively, through conventional (TsCl/NaOH) strategy
on the corresponding bis-amide precursors 6b′ and 17, respec-
tively.
The influence of the intramolecular distance between amidic
moieties and oxazoline rings also was evaluated. With this aim,
a new class of isopropylidene-bridged ligands 22 was designed
with the related synthesis involving the use of malonic derivative
19 as the starting material.13
Optimal conditions were obtained in the condensation of 2
and 2′ with 19 by using HBTU14 as the coupling agent that led
to 20 and 20′ in 43% yield. Then, after selective removal of
the benzylic groups by Pd/C catalyzed hydrogenolysis (balloon)
in methanol, the crude diacid adduct was coupled directly with
(S)-valinol 5a in the presence of HBTU/TEA to give 21a/21a′
in 62% and 81% yield (two steps) from 20 and 20′, respectively.
Finally, the Deoxo-Fluor based cyclization (DCM, 0 °C,
NaHCO3) proved its efficiency also with this class of compounds
furnishing the desired bis-oxazoline ligands 22a and 22a′ in
22% and 37% yield, respectively (Scheme 5).
Solid-State Structure of 1a. To gain more information about
the conformational features of the ligand and make reasonable
assumptions on its coordination abilities, the X-ray structure of
the title molecule was determined. The molecule 1a, which
contains the (R,R)-cyclohexyl-N,N-diamide inner core, has been
found in two conformations in the crystal. The molecular models
(A and B) are shown in Figure 2 with the same orientation of
the cyclohexyl backbone.
TABLE 1. Synthesis of Binaphthyl and DPEA-Based Ligands 12
and 14
The molecules, which have potential symmetry C2, exhibit
asymmetric conformations. Significant differences because of
packing effects are observed at the level of the oxazoline rings.
The two conformers are almost superimposable and maintain
C2 symmetry up to the amide groups. The asymmetric confor-
mation is stabilized in both molecules by an intramolecular
hydrogen bond between the N-H group in one appendage and
the carbonylic oxygen in the other (N(3)-H(41)‚‚‚O(4) in A
and N(7)-H(43)‚‚‚O(8) in B). The bond distances indicate an
interaction stronger in A (H(41)‚‚‚O(4), 2.14(3) Å) than in B
(H(43)‚‚‚O(8), 2.42(3) Å). Also, this difference is considered a
packing effect, the hydrogen bond being a soft interaction. It is
worth mentioning the tendency to coplanarity between amide
and pertinent oxazoline groups [dihedral angle 33.2(4)° and 6.7-
(6)° in A; 1.0(8)° and 5.3(6)° in B]. Interestingly, the largest
deviation from coplanarity is associated to the longer C(amide)-
C(oxazoline) distance (C(14)-C(15), 1.515(5) Å vs C(34)-
C(35), 1.479(5) Å) and to the stronger hydrogen bond. Although
the solid-state asymmetric conformation has not been detected
in solution even in non-hydrogen-bonding solvents (CH2Cl2),
it should be a preferred one among the transient conformations.
When the bonding abilities of 1a are considered, the solid-state
structure suggests that the amide nitrogens are unlikely to take
part in bonding to metal ions because their lone pairs are
delocalized in π bonding. This is indicated by the short value
of the N(amide)-C(amide) bonds (average value 1.32(1) Å)
compared to the N(amide)-C(cyclohexyl) value (average 1.46-
(1) Å). The tendency to interchain hydrogen bridging and the
hindered rotation around the amide-oxazoline bonds signifi-
entry
amine
R
yield (%)a diol 11/13b
yield (%)a ligandc
1
2
3
4
5
6
(R)-7
(R)-7
(R)-7
(S)-7
(S)-7
(R,R)-8
i-Pr
Ph
Bn
i-Pr
Bn
Ph
87 (11a)
89 (11c)
95 (11e)
97 (11a′)
86 (11e′)
95 (13)
61 (12a)
22 (12c)
69 (12e)
66 (12a′)
17 (12e′)
94 (14c)
a Isolated yields (purity >95% by HPLC). b Toluene, reflux, 48 h.
c Deoxo-Fluor, CH2Cl2, -10 °C f rt, NaHCO3, 5 h.
1
(16%, chemical purity >95%, H NMR dropped as a result).
Because of their intrinsic structural properties (i.e., dihedral
angles), enantiopure 1,2-diamines remarkably influence the
catalytic activity of many C1 and C2 chiral ligands.12 We have
accounted for the effect of different chiral diamino units on the
coordination chemistry of type-1 ligands by applying the
previously described methodology to commercially available
1,1′-binaphthyl-2-2′-diamine (7, DABN) and 1,2-diphenyleth-
ylene-diamine (8, DPEA) in enantiomerically pure form.
Here, the coupling between the diester intermediates 9 and
10 with the corresponding â-amino alcohols proceeded smoothly
providing the desired diols in 86-97% yield (Table 1).
Analogously, the following ring-closing procedure gave
ligands 12 and 14 in appreciable to excellent yields (up to 94%,
entry 6). Only in a few cases (12c, 12e′), the yields dropped
significantly (22% and 17%, respectively) because of the
required chromatographic purification of the reaction crude
product.
(13) Ceretti, S.; Luppi, G.; De Pol, S.; Formaggio, F.; Crisma, M.;
Toniolo, C.; Tomasini, C. Eur. J. Org. Chem. 2004, 20, 4188-4196.
(14) Carpino, L. A.; Imazumi, H.; El-Faham, A.; Ferrer, F. J.; Zhang,
C.; Lee, Y.; Foxman, B. M.; Henklein, P.; Hanay, C.; Mu¨gge, C.; Wenschuh,
H.; Klose, J.; Beyermann, M.; Bienert, M. Angew. Chem., Int. Ed. 2002,
41, 441-445.
Among the investigated ligands, the procedure failed only
with 1b′ (Scheme 3) and 18 with 1,2-phenylenediamine (15)
(12) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. ReV.
2000, 100, 2159-2231.
J. Org. Chem, Vol. 71, No. 17, 2006 6453

Albano et al.
SCHEME 3. Alternative Ring-Forming Method for the Synthesis of 1b′
SCHEME 4. Preparation of 1,2-Phenylendiamine Based Ligand 18
for novel Pd-mediated stereoselective transformations.5,15 The
protocol allows polyfuctionalized compounds (25) to be syn-
thesized in a stereocontrolled manner through the addition of
both soft and hard nucleophiles to chiral π-allylpalladium
intermediates (24) (eq 1).
SCHEME 5. Multistep Synthesis of Malonyl Derivative
Ligands 22
The AAA of 23a was chosen as the model reaction, and an
initial survey of reaction media was carried out in the presence
of the diastereoisomeric ligands 1a and 1a′. The reactions were
conducted with 8 mol % of chiral Pd complex, which was
synthesized in situ by stirring the ligand and [Pd(η3-C3H5)Cl]2
in 2:1 ratio in the presence of BSA/KOAc as the base system.
The results obtained in several solvents are summarized in
Scheme 6.
From an analysis of the data, several conclusions can be
drawn. First, analogously to the findings described by Pfaltz
and co-workers in the Mo-mediated AAA,7 ligand 1a′ proved
to be the matched system among the possible stereochemical
combinations because it constantly delivered 25a (Nu ) DMM)
with both yield and ee higher than 1a. As expected, the
stereochemistry of the process was strongly affected by the
reaction medium,16 which was the choice solvent THF. Under
these conditions, product 25 was isolated in quantitative yield
and with ee up to 91% in the case of 1a′. The overall efficiency
of this catalytic system also relies on the reaction temperature.
cantly reduces the conformational liberties of the molecule and
makes more probable interchain chelation to metal centers
(O(carboxamide)‚‚‚N(oxazoline) or N(oxazoline)‚‚‚N(oxazoline)).
The following contacts present in the conformation frozen in
the crystal are worth attention: O(4)‚‚‚N(2), 3.522(4) Å and
O(8)‚‚‚N(5), 3.700(4) Å. These values easily can adjust to the
ideal one in the case of coordination to a metal ion (ca. 3.06 Å)
(see further on). Although these considerations are given for
1a, they also are valid for the diastereoisomeric 1a′, which
exhibits the same trans-stereochemistry between the two ap-
pendages.
Pd-Catalyzed AAA. The AAA of 1,3-diphenyl-2-propenyl
carbonate (23a) is employed largely as a bench test reaction
(15) Pfaltz, A. Acc. Chem. Res. 1993, 26, 339-345.
6454 J. Org. Chem., Vol. 71, No. 17, 2006

Characterization of Chiral Bis-oxazoline-amides
FIGURE 2. Molecular structure for the A and B conformers of 1a determined by X-ray diffraction.
TABLE 2. Results of AAA of 23a with Dimethyl Malonate (DMM)
Catalyzed by [PdCl(C3H5)]2/12, 14c, 18a, 22
SCHEME 6. Synthesis of the Ligand 30
entrya
L
yield (%)b
ee (%)c
config.d
1
2
3
4
5
6
7
8
9
12a
12a′
12c
12e
12e′
14
18
22a
22a′
86
80
85
40
86
71
75
81
81
9
25
24
8
28
42
42
0
S
S
R
S
S
R
S
10
S
a All the reactions were carried out in THF under reflux. Reaction time
16 h. b Isolated yields after flash chromatography. c Determined by chiral
HPLC (Chiralcel AD). d The absolute configuration was assigned by
comparing the optical rotation value with literature.
When the asymmetric alkylation in THF was run at rt, 25a was
isolated only in traces together with decomposition products.
Products with opposite absolute configurations were system-
atically isolated by using 1a and 1a′, respectively, indicating
the relevant role of the backbone stereocenters on the final
stereochemical outcome. Careful anhydrous conditions were
required for the best results. In fact, when we performed the
AAA of the more stable 23b in aqueous medium (THF/H2O
9:1), only 10% of (S)-25a was obtained (stoichiometric reaction)
but with high enantiomeric excess (92% ee). These findings
suggest a persistence of stereoinduction in the active Pd complex
even in water and degradation of the active species during the
catalytic cycle. Finally, the concentration of the catalyst was a
factor influencing the final outcome in 25. High catalyst
concentrations caused rapid formation of black, insoluble Pd
species, which are in equilibrium with soluble catalytically active
but poor stereoselective Pd(0) clusters.17 The optimal reaction
conditions (1a′/THF/reflux, 13 mM catalyst concentration)
finally were employed in the presence of allyl acetate (()-23b.
In these conditions, chemical as well as optical yields compa-
rable to (()-23a were obtained (94% yield, 92% ee).
The effects of the type of chiral diamine in the ligand and
the distance between oxazoline ring and amide function on the
overall stereoefficiency of the process were systematically
assessed by testing ligands 12, 14, 18, and 22 under optimal
conditions (Table 2).
With regard to stereoselectivity, binaphthyl- (12), DPEA (14),
and 1,2-phenylendiamine-(18) based ligands delivered poor
enantiocontrol (8-42%, entries 1-7) with the highest ee
obtained when (R)-DPEA was used as the chiral scaffold. In
the cases of ligands 22a and 22a′, an unsatisfactory enantio-
control also was obtained (0% and 10% ee, respectively, Table
2).
To properly estimate the role of the oxazoline substitution
on the enantiocontrol of the reaction, the entire library of
cyclohexyl-based ligands 1 was tested under optimal reaction
conditions (Table 3).
(16) Interestingly, the ESI-MS performed at low potentials (10 eV) by
dissolving each complex [(1a′)-Pd(η3-C3H5)][BF4] and [(1a′)-Pd(η3-1,3-
Ph2C3H3)][BF4] in CH3CN showed the presence of [(CH3CN)2-Pd(η3-
C3H5)]+ (m/z 229) and [(CH3CN)2-Pd(η3-1,3-Ph2C3H3)]+ (m/z 381),
respectively. Such evidence indicates that CH3CN can be considered a
competitive ligand for the palladium center in respect to 1a′ justifying the
significant drop in catalytic activity recorded in acetonitrile under reflux
(yield, 59%; ee, 47%).
From an analysis of the listed results, several conclusions
can be drawn. First, the relevant role of the chiral diamine
backbone in controlling the stereochemistry of the reaction
outcome appears evident. By use of the ligand 1d without
stereocenters in the oxazoline ring, 25 was isolated in compa-
rable ee (82%, entry 3 in Table 3).
(17) For representative examples of the role of ligand-free Pd nanopar-
ticles in catalyzing C-C bond forming reactions, see: (a) Reetz, M. T.; de
Vries, J. G. Chem. Commun. 2004, 1559-1563. (b) Cassol, C. C.; Umpierre,
A. P.; Machado, G.; Wolke, S. I.; Dupont, J. J. Am. Chem. Soc. 2005, 127,
3298-3299.
The substituents in the oxazoline units were also found to
play an important role. In particular, while phenyl groups took
part in the enantiocontrol only marginally (i.e., ee ) 80% with
1c, ee ) 82% with 1d, entries 2 and 3 in Table 3), hindered
J. Org. Chem, Vol. 71, No. 17, 2006 6455

Albano et al.
TABLE 3. Cyclohexyl-Based Ligands 1 as Chiral Promoters in the
AAA of 23aa
aliphatic groups (i.e., i-Pr and t-Bu) contributed to the enan-
tiocontrol of the reaction as well as the stereocenters on the
cyclohexyl ring (entries 1 and 4 in Table 3). Finally, among
the ligands with matched configurations (S,S-diamine and
S-amino alcohol), the one derived by 1b′ provided the highest
enantiocontrol (yield ) 83%, ee ) 98%).
The best results were finally achieved by applying the ligand
of choice (1b′) to the AAA with 1,3-di(4′-chlorophenyl)allyl
carbonate (23c) and the aliphatic unhindered 1,3-dimethylallyl
carbonate (23d). In both cases, the corresponding alkylated
compounds (25c,d) were isolated in good yields and remarkable
ee’s (93% and 80%, respectively, eq 2).
(R,R)b
yield (%)c
(S,S)b
yield (%)c
entry
R1
R2
ee (%)d
ee (%)d
1
2
3
4
i-Pr
Ph
Me
t-Bu
H
H
Me
H
58
99
81
62
30 (R)
80 (R)
82 (R)
44 (S)
99
98
91 (S)
75 (S)
83
98 (S)
a All the reactions were carried out in THF under nitrogen atmosphere
by employing 8 mol % of catalyst (ratio Pd/L ) 1:1) under reflux. Reaction
time 16 h. b Configuration of the DACH-based chiral backbone. c Isolated
yields after flash chromatography. d Determined by chiral HPLC (Chiralcel
AD). The absolute configuration was assigned by comparing the optical
rotation value with literature.
[(1a′)2-Pd(η3-C3H5)]+ (50 eV, 931 m/z) and [(1a′)2-Pd2(η3-
C3H5)2(-H)]+ (50 eV, 1096 m/z).
Palladium Allylic Complexes. Although no crystallographic
evidence has been reported so far, Trost modular ligands are
believed to coordinate the [Pd(η3-allyl)] fragments through a
P,P-coordinating mode (26a) forming a 13-membered metalla-
cycle (eq 3).5
The corresponding [(1a′)-Pd(η3-1,3-Ph2C3H3)]‚[BF4] was
synthesized and isolated following the aforementioned protocol
by employing [Pd(η3-1,3-Ph2C3H3)(µ-Cl)]2 as the palladium
19
source (THF-CH2Cl2 6:1, rt, 87% yield). The ESI-MS analysis
revealed the presence of [(1a′)-Pd(η3-1,3-Ph2C3H3)] cation (m/z
1
691) as the major compound. The H NMR spectra of the
complex in CD2Cl2 and [d8]THF (rt, 13 mM) showed only one
well-defined set of signals corresponding to a C1-symmetrical
organometallic complex in 1:1 ratio between [Pd(η3-1,3-
Ph2C3H3)] unit and 1a′ (see Experimental Section for NMR
data). VT-NMR experiments in CD2Cl2 were conducted and a
coalescence of the signals attributable to the allyl protons (H
central and H anti) was observed when the temperature was
lowered to -70 °C. At -90 °C, two distinct sets of signals for
these protons were detected and assigned (allyl coupling
constant, J ) 11.0 Hz),20 to the 1,3-disubstituted-syn-syn-allyl
systems (1:1 ratio). By increase of both the temperature
(50 °C, [d8]THF, 13 mM) and the concentration (23 °C, [d8]-
THF, 64 mM) of the complex, no significant change in the
spectra was observed indicating the absence of oligomeric
species in solution. This fact was ascribed to the higher sterical
hindrance of the diphenylallyl unit with respect to [η3-C3H5],
which prevents the formation of oligomeric species in solution.
Interestingly, by carrying out the synthesis of [(1a′)-Pd(η3-
1,3-Ph2C3H3)]‚[BF4] under catalytic conditions (THF, reflux,
13 mM, 7h), we obtained the same species synthesized at rt.
NMR and IR experiments also were conducted to detect
intramolecular H-bonds, which could be responsible for the C1-
symmetry in the [(1a′)-Pd(η3-1,3-Ph2C3H3)]‚[BF4] complex in
solution. Both chemical shift and temperature coefficients (∆δ/
∆T) of the N-H amidic protons usually are employed to detect
the presence of intramolecular H-bonds.21 In the C1-symmetrical
conformation observed by NMR spectroscopy, the chemical shift
To gain information regarding the bonding modes of our class
of multidentate chiral ligands (26b), spectroscopic as well as
X-ray crystallographic analyses were performed on several
[(1a′)-Pd(η3-allyl)] complexes.
Here, 1a′ and [Pd(η3-C3H5)Cl]2 (2:1 molar ratio) were stirred
at rt in the appropriate solvent for 3 h followed by exchange
reaction with AgBF4. The final cationic allyl complex was
recovered after elimination of the insoluble materials and solvent
evaporation (73% yield). The 1H NMR data of a 13 mM solution
of [(1a′)-Pd(η3-C3H5)]‚[BF4] (optimal concentration for the
catalytic AAA) at rt in CD2Cl2 and [d8]THF appeared difficult
to rationalize because of the multitude of signals. However, eight
signals in the amidic proton region (7.2-8.8 ppm) were present
in CD2Cl2 and only six in [d8]THF. In both cases, by changing
the temperature (from 30° to -90° in CD2Cl2 and from 50° to
-90° in [d8]THF) as well as concentrating the solution of the
complex (30 mM), no coalescence was observed, but we
detected a change in the relative intensities of these amidic
signals. We assumed, in agreement with the recent findings by
Lloyd-Jones and co-workers on Pd-allyl complexes with Trost’s
ligands,18 the presence in solution of monomer-oligomer
equilibria, which are affected by both temperature and concen-
tration. Proof of oligomeric species derived from the ESI-MS:
(19) Von Matt, P.; Lloyd-Jones, G. C.; Minidis, A. B. E.; Pfaltz, A.;
Macko, L.; Neuburger, M.; Zehnder, M.; Ru¨egger, H.; Pregosin, P. S. HelV.
Chim. Acta 1995, 78, 265-284.
(20) Canal, J. M.; Gomez, M.; Jimenez, F.; Rocamora, M.; Muller, G.;
Dunach, E.; Franco, D.; Jimenez, A.; Cano, F. H. Organometallics 2000,
19, 966-978.
(18) (a) Fairlamb, I. J. S.; Lloyd-Jones, G. C. Chem Commun. 2000,
2447-2448.
(21) Belvisi, L.; Bernardi, A.; Manzoni, L.; Potenza, D.; Scolastico, C.
Eur. J. Org. Chem. 2000, 2563-2569.
6456 J. Org. Chem., Vol. 71, No. 17, 2006

Characterization of Chiral Bis-oxazoline-amides
of one amidic proton was non-concentration-dependent (δ(N-
H) ) 8.32 ppm at 13, 5, and 1 mM, CD2Cl2), while the chemical
shift of the second one was markedly affected by the concentra-
tion (δ(N-H) ) 7.35 ppm at 13 mM and 6.95 ppm at 4 and 1
mM, CD2Cl2). This suggests that at least one amidic proton in
the Pd complex was engaged in an intermolecular hydrogen
bond interaction, which breaks up at high dilution. Moreover,
the non-interacting nature of this proton at low concentrations
(i.e., 1 mM) was confirmed by a low coefficient temperature
(-1.0 ppb/K). The non-concentration-dependent amidic proton
was not engaged in any hydrogen bond interaction, as demon-
strated by the low coefficient temperature (-2.0 ppb/K) and
high ∆δ(N-H) (>0.2 ppm in absolute value) upon addition of
a competitive solvent ([d6]DMSO, 25 equiv). In comparison
to free 1a′, the characteristic downfield chemical shift (1.08
ppm) of the N-H amide proton in the [(1a′)-Pd(η3-allyl)]
complex may be explained by assuming the coordination of the
carboxamide oxygen to the Pd atom.22 Solution IR spectroscopy
confirmed these conclusions with the complex showing two
distinct N-H stretching at 3372 and 3290 cm-1 (26 mM, CH2-
Cl2). By dilution of the solution (1 mM), the N-H stretching
at 3372 cm-1 did not change, whereas the signal at 3290 cm-1
FIGURE 3. Testing the effect of the solvent in the AAA of 23a under
reflux conditions.
In complex 29, the bis-(N,O)-complexation mode is present.
In fact, each of the two [Pd(η3-1,3-Ph2C3H3)] units is bonded
to the ligand through the oxazoline nitrogen and the amidic
oxygen in each pendant forming two planar five-membered
palladacycles with opposite stereochemistry of the allyl ligands
(endo-Pd(1)(η3-1,3-Ph2C3H3), exo-Pd(2)(η3-1,3-Ph2C3H3)). No
significant differences in the allyl-metal interactions of each
diphenylallyl unit was observed as shown by the Pd-C bond
lengths [C(21)-Pd(1) 2.171(8); C(22)-Pd(1) 2.110(9); C(23)-
Pd(1) 2.12(1); C(36)-Pd(2) 2.14(1); C(37)-Pd(2) 2.08(1);
C(38)-Pd(2) 2.18(1)]. Unfortunately, this species never has
disappeared. At the same time, a sharp peak (3557 cm-1
)
appeared in the non-hydrogen-bonded N-H stretch region.
Moreover, significant changes (lower frequencies) in both CdN
and CdO stretchings were observed in comparison to the new
ligand, supporting a N,O-coordination mode (∆νCdO ) 20 cm-1
;
1
1
∆νCdN ) 16 cm-1). The close resemblance between the H
NMR/IR spectra in CD2Cl2 and [d8]THF allowed us to conclude
that the same organometallic species is present in both sol-
vents.23
been detected in the H NMR spectra of the allylic complex
synthesized and probably derives from the initially formed
complex after long standing in solution. Although 29 was not
the expected species, its formation demonstrates that the N,O-
bonding mode of type-1 ligands should be taken into account.
To verify the role of the N,O-bonding mode on the active
enantiodiscriminating complex in solution, we synthesized the
model mono-oxazoline ligand 30. This ligand allows only 26c-
type coordination geometry. The synthesis of C1-amido-oxazo-
line 30 was conducted by initial condensation of chlorooxocetate
3 with BnNH2 to give the corresponding amido-ester 28 (85%
yield). After the synthesis of the (S)-valinol amide 29 (95%
yield), the final ring-closing reaction was effectively carried out
through the Deoxo-Fluor method (yield 65%, Scheme 6).
Interestingly, when 30 was used as a chiral ligand in the
model reaction (THF, reflux), (S)-25a was isolated with only
19% yield and in nearly racemic form (10% ee). The poor
optical and chemical yields recorded tend to exclude 26c as a
catalytically active coordination mode. Therefore, it is evident
that both sidearms of the ligand are involved during either the
assembling of the Pd-catalyst or the enantiodiscriminating step
of the process. Further indications came also from the use in
catalysis of the Boc-mono-oxazoline 34 that was readily
synthesized in three steps starting from desymmetrized C1
symmetrical 3125 in 38% overall yield (Scheme 7).
In light of this evidence, some tentative molecular structures
for the precatalytic species present in solution can be drawn
(eq 4).
In these structures, 26c describes a C1-symmetrical thermo-
dynamically stable five-membered palladacycle with N,O com-
plexation mode, while 26d represents an alternative tentative
coordination mode with the two binding heteroatoms belonging
to different pendants.22,24,25
To gain some insight into the structure of the species present
in solution, we studied one of the crystals precipitated from
a THF solution after 30 d at 4 °C by X-ray diffraction.
The molecular formula was found to be [(1a′)-Pd2(η3-1,3-
Ph2C3H3)2]‚[BF4]2 (29) (Figure 4).
By use of 34 as a chiral ligand in the model reaction,
(S)-25a was isolated in 85% yield and 70% ee. This result
supports the Pd complexation by the carbamate carbonyl oxygen
in the catalytic species and suggests an operative type-26d
coordination mode of 1a′ justified also by the observed solid-
state conformation of 1a discussed above. The slight difference
in ee between 1a′ and 34 could be attributed to steric differences
between substituted oxazoline rings and the BOC protecting
group.
(22) Butts, C. P.; Crosby, J.; Lloyd-Jones, G. C.; Stephen, S. C. Chem.
Commun. 1999, 1707-1708.
(23) Both chemical shift and N-H stretching values of the amidic proton
were non-concentration-dependent (δ(N-H) ) 8.08 ppm and ν(N-H) )
3269 cm-1 at 13 and 1 mM, respectively, in [d8]THF).
(24) For examples of chelation modes for Trost and analogous hybrid
ligands to Pd see: (a) Trost, B. M.; Breit, B.; Organ, M. G. Tetrahedron
Lett. 1994, 35, 5817-5820.
Finally, although the data collected call for a type-26d
coordination mode with the Pd atom in the catalytic species,
(25) Kim, Y. K.; Lee, S. J.; Ahn, K. H. J. Org. Chem. 2000, 65, 7807-
7813.
J. Org. Chem, Vol. 71, No. 17, 2006 6457

Albano et al.
FIGURE 4. Molecular structure for the [(1a′)-Pd2(η3-1,3-Ph2C3H3)2]2+ cation 29, determined by X-ray diffraction. Selected bond lengths (Å) and
angles (deg): O(1)-Pd(1) 2.175(6), N(3)-Pd(1) 2.146(7), O(3)-Pd(2) 2.187(6), N(4)-Pd(2) 2.104(8), O(1)-Pd(1)-N(3) and O(3)-Pd(2)-N(4)
77.5(3).
SCHEME 7. Synthesis of the C1-Symmetrical Ligand 34
(5.5 mg, 13 × 10-3 mmol), and 1.0 mL of anhydrous THF. The
mixture was stirred at room temperature for 30 min and then allyl
carbonate (0.16 mmol), dimethyl malonate (92 µL, 0.81 mmol),
BSA (118 µL, 0.48 mmol), and a catalytic amount of anhydrous
KOAc were added sequentially. The reaction was stirred overnight
under reflux and after 16 h was judged complete by TLC analysis.
Then, the reaction was quenched with a saturated solution of
NaHCO3 (3 mL), the two phases were separated, and the aqueous
phase was extracted with AcOEt (3 × 5 mL). Finally, the organic
layers were collected, dried with Na2SO4, and then concentrated
under reduced pressure. The desired product (S)-25a was isolated
as a yellow oil in 83% yield (43 mg) after flash chromatography
(cHex/Et2O 90:10). The ee of the product (98%) was determined
by chiral HPLC (Chiralcel AD: IPA/n-Hex 10:90, 1.0 mL/min flow,
214 nm, RtR: 9.3 min; RtS: 12.6 min); [R]25D ) -8.8 (c ) 0.6 in
CHCl3), lit (R)-25a [R]25 ) +19.2 (c ) 1.3 in CHCl3).26
D
we cannot rule out that the C2-symmetrical N,N-Pd motif might
play an active role during the enantiodiscriminating step of the
catalytic cycle being in rapid equilibrium with 26d.
Acknowledgment. This work was supported by M.I.U.R.
(Rome), PRIN project “Sintesi e stereocontrollo di molecole
organiche per lo sviluppo di metodologie innovative di interesse
applicativo” and “Nuove strategie per il controllo delle rea-
zioni: interazione di frammenti molecolari con siti metallici in
specie non convenzionali”, FIRB Project (Progettazione, preparazi-
one e valutazione biologica e farmacologica di nuove molecole
organiche quali potenziali farmaci innovativi), and the University
of Bologna.
Conclusions
In conclusion, a new flexible three-step procedure for the
synthesis of C2-bis-oxazoline-amide ligands is described. The
library of compounds was tested in Pd-catalyzed AAA isolating
the desired products with high enantiomeric excess (ee up to
98%). Combined crystallographic and spectroscopic investiga-
tions call for a C1-symmetrical N,O-chelating mode to be
operating during the enantiodiscriminating step of the reaction.
By virtue of the flexibility of the chiral ligands 1, their
employment in different asymmetric catalytic transformations
is under way.
Supporting Information Available: Experimental procedures
and analytical and spectral characterization data for all the
compounds, and CIF data for 1a and 29. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO060767V
Experimental Section
Representative Procedure for Pd-catalyzed AAA (in situ
procedure). A 25 mL two-necked flask was charged under nitrogen
atmosphere with [Pd(η3-C3H5)Cl]2 (2.3 mg, 6.4 × 10-3 mmol), 1b′
(26) Leutenegger, U.; Umbricht, G.; Fahrni, C.; von Matt, P.; Pfaltz, A.
Tetrahedron 1992, 48, 2143.
6458 J. Org. Chem., Vol. 71, No. 17, 2006