Tridentate chiral NPN ligands based on bis(oxazolines) and their use in Pd-catalyzed enantioselective allylic substitution in molecular and ionic liquids

Article abstract of DOI:10.1016/j.tet.2011.05.079

NPN ligands based on the bis(oxazoline) skeleton can be prepared by a divergent method, which allows a high modularity both in the type of phosphorous group (phosphinite, phosphate, phosphane) and the substitution in the methylene bridge. The Pd complexes

Full text of DOI:10.1016/j.tet.2011.05.079

Tetrahedron 67 (2011) 5402e5408
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tridentate chiral NPN ligands based on bis(oxazolines) and their use in
Pd-catalyzed enantioselective allylic substitution in molecular and ionic liquids
a
b
b
a
,
b
c
*
ꢀ
ꢀ
M. Rosa Castillo , Sergio Castillon , Carmen Claver , Jose M. Fraile , Aitor Gual , Marta Martín ,
a,
c
*
ꢀ
Jose A. Mayoral , Eduardo Sola
a Department of Organic Chemistry, ISQCH and IUCH, Universidad de ZaragozadC.S.I.C., C/Pedro Cerbuna 12, E-50009 Zaragoza, Spain
b Fac. Química, Universitat Rovira i Virgili, C/Marcel$lí Domingo s/n, E-43007 Tarragona, Spain
c Department Coordination Chemistry and Homogeneous Catalysis, ICMA, Universidad de ZaragozadC.S.I.C., C/Pedro Cerbuna 12, E-50009 Zaragoza, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 April 2011
Received in revised form 16 May 2011
Accepted 18 May 2011
Available online 26 May 2011
NPN ligands based on the bis(oxazoline) skeleton can be prepared by a divergent method, which allows
a high modularity both in the type of phosphorous group (phosphinite, phosphate, phosphane) and the
substitution in the methylene bridge. The Pd complexes of these ligands can efficiently promote the
allylic substitution both in molecular solvents and ionic liquids, with important effect of the nature of
ligand, which also controls the partial recovery of the Pd catalyst in ionic liquid.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
NPN ligands
Bis(oxazolines)
Palladium
Allylic substitution
Ionic liquids
1. Introduction
C2-Symmetric bis(oxazolines)1 and in general oxazoline-
containing chiral ligands2 have been extensively used in enantio-
selective catalysis. In spite of this, the development of new chiral
ligands of this family to be used for specific applications is a matter
of great interest. Phosphinooxazolines (PHOX, Fig. 1)3 became very
popular due to the success as chiral ligands for different enantio-
selective reactions, such as allylic substitutions, Heck coupling, or
hydrogenations, and a plethora of structural variations have been
described, including the presence of additional stereogenic ele-
ments (atoms, axis, planes), and the substitution of phosphane
group by phosphonite, phosphite, or phosphoramidate.
However the number of tridentate ligands based on bis(oxa-
zolines) is rather limited. Apart from the well known pyr-
idinebis(oxazoline) (pybox) family,4 other coordinating groups have
been inserted between the two oxazoline rings, such as amine5 or
carbazole6 to produce NNN-ligands, ether or dibenzofuran to pro-
duce NON-ligands,7 dibenzothiophene8 to produce NSN ligands,
phenyl9 leading to NCN ligands, and phosphine10 or phosphite11 to
produce NPN ligands (Fig. 1). Even more scarce is the number of
O
O
O
O
O
N
N
N
N
N
Ar2P
N
4
R
R
R
R
pybox
NCN-ligand9
R
N
3
PHOX
P
O
O
Ph
N
N
N
NPN10
X
R
R
X
O
O
O
O
N
N
O
O
N
P
O
O
R
R
R
Ph
R
N
X = NH,6 O,7 S8
X = NH,5 O,7 PPh10
NPN11
R'
O
X
O
N
O
O
O
X =
N
N
N
N
N
OH
R
R
-COONa
R
R
12
trisox
* Corresponding authors. Tel.: þ34 976 761000x3514; e-mail addresses:
Fig. 1. Phosphinooxazolines (PHOX) and different tridentate ligands based on
bis(oxazolines).
jmfraile@unizar.es (J.M. Fraile), mayoral@unizar.es (J.A. Mayoral).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.079

M.R. Castillo et al. / Tetrahedron 67 (2011) 5402e5408
5403
tridentate ligands with the additional coordinating group in
a sidearm of the central bridge of the bis(oxazoline) skeleton.
Tris(oxazolines)12 can be included in this category, together
with a limited number of ligands functionalized with phenol, ke-
tone, carboxylate or pyridine groups13 (Fig. 1). However, up to date
no phosphorous-containing groups had been included in this type
of sidearms tridentate ligands.
85%. Phosphite/oxazolines bearing bulky phosphite groups have
been described as excellent ligands for enantioselective allylic
substitutions.35 In view of that, the same bulky group was in-
troduced by reaction of the hydroxymethylated bis(oxazolines)
(3a,b) with the corresponding phosphorochloridite.36 Lower yields
of the final ligands (5a,b) were obtained (around 28%) probably due
to the high steric hindrance introduced by this group. In all these
cases, the presence of a eCH2eOe spacer between the bis(oxazo-
line) bridge atom and the phosphorous would lead to the formation
of seven-membered chelates.
Alternatively the central bridge can be bromomethylated by
reaction with dibromomethane in basic medium. The bromomethyl
derivative 7a was obtained with 94% yield, and subsequent reaction
with KPPh2 led to the corresponding phosphane 8a. In this way
6-membered chelates would be possible.
The palladium-catalyzed asymmetric allylation reaction14 has
been the subject of intense studies15 dealing with the design,
synthesis and use of a huge number of chiral non-racemic ligands.
Moreover, it is used as benchmark reaction to test newly developed
chiral ligands,16 as in the case of some oxazoline-containing tri-
dentate NNN,17,18 NON,7 NSN,8 and NPN19 ligands (Fig. 1).
One aspect still to be solved in allylic substitution is that con-
cerning to the catalyst recovery. In the case of heterogeneous cat-
alysts, immobilization of bidentate NN ligands onto polymeric
supports leads to problems in activity, enantioselectivity, and
mainly in recovery of the catalysts.20 Better recoverability was
obtained with supported tetradentate pyridylamides21 or with
a bidentate N,P-ligand.22 Recovery of homogeneous catalysts has
been carried out by modification of bis(oxazolines) with fluorinated
ponytails23 or by functionalization of a phosphite/oxazoline de-
2.2. Catalytic results in enantioselective allylic substitution
Benchmark reaction was that of (E)-1,3-diphenylprop-2-enyl ac-
etate with diethyl malonate in dichloromethane, using N,O-bis(tri-
methylsilyl)acetamide(BSA)andsodiumacetateasabase, conditions
suitable for comparison with most of results described in the litera-
ture. Palladium complexes were prepared in situ with ligand/Pd ratio
1.5 and results are gathered in Table 1 (entries 1e6). The presence of
the phosphorus atom noticeably increased the catalytic activity,
leading to total conversions after short reaction times (up to 4 h),
whereas analogous bis(oxazoline) and azabis(oxazoline) required
very long reaction times (typically 2e7 days7,18,30). It is remarkable
the result obtained with 8a, as only 15 min are required to obtain
quantitative yield in dichloromethane (entry 6), in the same order
than the best results described in the literature for phosphinoox-
azoline ligands (10 min to 24 h).35b,37ꢀ39
The coordination of Pd to at least one oxazoline ring is dem-
onstrated by the obtained enantioselectivity, whose value is
strongly influenced by the nature of the phosphorous group. Higher
enantiomeric excess was obtained in the order phosphite (4ae5a,
52e56% ee, entries 1 and 3)<phosphinite (6a, 91% ee, entry 5)
<phosphane (8a, 95% ee, entry 6). It is worthy to note that results
with ligand 8a, both in activity and selectivity, are comparable with
those obtained with the classical phosphinooxazoline ligand (98%
yield and 98% ee after 1 h reaction),37 the analogous bidentate NP
ligand either without (94% yield, 86% ee) or with (86% yield, 94% ee)
an additional stereogenic center,40 and the previously described
NPN ligand (74% yield, 92% ee).19 The substitution of methyl
by benzyl group in the bridge between the oxazolines has a deep
influence in the enantioselectivity, that increases from 52e56% ee
with 4ae5a to 81e83% ee with 4be5b (entries 2 and 4).
When the reaction was carried out in an ionic liquid, [bmim]
[PF6], reaction times required for total conversion were similar to
those required in the molecular solvent, with the only exception of
8a, that required 2.5 h (entry 17) instead of the 15 min in CH2Cl2. It
is worth noting that the activating role of phosphorous was much
higher than that showed by PPh3 in the experiments with the same
P/Pd ratio (1.5).30,31 With regard to enantioselectivity, the effect of
the nature of the phosphorous group follows the same trend:
phosphite (4ae5a, 13e34% ee, entries 7 and 11)<phosphinite (6a,
68% ee, entry 15)<phosphane (8a, 92% ee, entry 17). As can be seen
enantioselectivity is in general lower than that obtained in
dichloromethane. The inclusion of a benzyl substituent in the
bridge also improves enantioselectivity 37 (4b, entry 9) versus 13%
ee (4a, entry 7) and 57 (5b, entry 13) versus 34% ee (5a, entry 11). To
sum up the best ligand in dichloromethane, 8a, is also the best one
in ionic liquid with almost the same enantioselectivity (92% ee,
entry 17). This overall result improves the best one described in the
literature with ionic liquids (31% yield and 92% ee after 5 h with
iPr-Phosferrox).27b
rived from D-glucosamine with amino groups, allowing extraction
at different pH.24 In both cases recycling problems were found
either in activity or enantioselectivity.
In spite of the quick expansion in the use of ionic liquids as re-
action medium,25 their application to allylic substitution is rather
scarce26 and very few enantioselective examples are described in
the literature.27 Ferrocenyl-based diphosphines and phosphinoox-
azolines, as well as BINAP, were tested as ligands. First recovery was
only partially successful, with similar or slightly reduced enantio-
selectivity and a significant drop in activity in most cases. In spite of
the good results obtained in allylic substitution with simple
bis(oxazoline)28 and azabis(oxazoline)29 ligands, their use in ionic
liquids30 leads to either no reaction at all or no enantioselectivity in
case of using triphenylphosphine as additional activating agent.31
In this paper we describe the development of a family of highly
modular tridentate NPN ligands based on bis(oxazolines) and their
use to promote the Pd-catalyzed reaction between (E)-1,3-
diphenylprop-2-enyl acetate and diethyl malonate in ionic liquids.
2. Results
2.1. Synthesis of NPN ligands based on bis(oxazolines)
The synthetic strategy is shown in Scheme 1. In the previously
described methods to include an additional coordinating group as
sidearm of the central methylene bridge of bis(oxazoline),13 the
inert alkyl group (methyl in the literature examples) is introduced
from the starting malonate used for bis(oxazoline) synthesis, and
any variation of this group would require starting the synthetic
route from another substituted malonate. In an attempt to introduce
higher modularity, the synthetic route was started from the easily
available methylenebis(oxazoline) 1,32 whereas the inert alkyl group
and the functionalized sidearm were sequentially introduced.
The treatment of the starting bis(oxazoline) 1 with equimolecular
amounts of potassium tert-butoxide and either methyl iodide or
benzyl bromide leads to the monoalkylated ligands (2a,b) in high
yields. This parameter was introduced to test the effect of bulkiness
in that position, given the importance observed in the case of
cyclopropanation reactions with the dialkylated ligand.33 Hydrox-
ymethylation was performed with paraformaldehyde in the pres-
ence of triethylamine as a base,34 leading to the intermediates 3a,b.
The hydroxyl group can be easily modified with (EtO)2PCl
i
or Pr2PCl, to obtain the corresponding phosphite (4a,b) or phos-
phinite (6a) modified bis(oxazolines), respectively, with yields over

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M.R. Castillo et al. / Tetrahedron 67 (2011) 5402e5408
R
O
O
OP(OEt)2
O
O
1
N
N
N
N
4
i)
tBu
iii)
R
tBu
R
H
PPh2
O
Br
O
OH
O
O
O
O
O
O
vi)
ii)
vii)
iv)
O
P
N
tBu
N
N
N
N
N
N
N
R
O
O
O
O
2
tBu
7a
3
8a
a: R = Me
b: R = CH2Ph
N
N
v)
N
5
OPiPr2
O
O
N
6a
Scheme 1. Synthesis of NPN ligands based on bis(oxazolines). Reagents and conditions: (i) t-BuOK/THFþMeI (or benzyl bromide), reflux,
4 h; (ii) paraformaldehyde/
0
0
ꢁ
CH2Cl2þdioxaneþH2OþEt3N/THF, rt, 3 days; (iii) MS 4 A/toluene rt, 8 h; 4-dimethylaminopyridineþ(EtO)2PCl, rt, 18 h; (iv) 4-dimethylaminopyridine/tolueneþ(3,3 ,5,5 -tetra-tert-
i
0
0
ꢁ
butyl-1,1 -biphenyl-2,2 -diyl)phosphorochloridite, rt, overnight; (v) MS 4 A/toluene rt, 8 h; 4-dimethylaminopyridineþ Pr2PCl, rt, 18 h; (vi) n-BuLi/THFþCH2Br2, reflux, 4 h; (vii)
KPPh2/THF, 0 ꢁC, 1 h.
Table 1
electronic properties of this arm can be represented by the PdeP
bond length in model complexes with analogous monodentate
phosphine ligands41 (Fig. 2). The obtained enantiomeric ratio fits
quite well (r¼0.981) with this parameter (Fig. 3), showing that
electronic properties of phosphorous group are more important
than the size of substituents, as demonstrated by the similar result
of 4a and 5a, or the PPdN chelate size (7 in 6a, 6 in 8a), which has
only marginal influence. The same correlation (r¼0.967) with the
same slope can be found for enantioselectivity obtained in ionic
liquid (Fig. 3). Hence we can argue that the same electronic effects
are controlling the enantioselectivity in both types of solvent, and
that the change of solvent affects in the same way to all the com-
plexes. In contrast with other steric features, the substitution
of methyl by benzyl group in the bridge between the oxazolines
has a deep influence, probably due to conformational changes
in the oxazoline moiety. The double benzyl substitution had
shown a slightly positive effect in bis(oxazolines)18 that contrasts
with the negative effect on copper catalyzed enantioselective
cyclopropanation.32
Results of allylic substitution with NPN ligands based on bis(oxazolines) in molec-
ular solvents and ionic liquids
Entry
Liganda
Solvent
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
4a
4b
5a
5b
6a
8a
4a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
[bmim][PF6]
Reuse
[bmim][PF6]
Reuse
[bmim][PF6]
Reuse
[bmim][PF6]
Reuse
[bmim][PF6]
Reuse
[bmim][PF6]
Reuse
3
3
1.5
4
3
0.25
4
100
100
100
100
100
100
100
50
100
100
100
<10
100
30
52
83
56
81
91
95
13
8
37
29
34
4
57
56
68
32
92
54
168
3
9
4b
5a
5b
6a
8a
10
11
12
13
14
15
16
17
18
17
1.5
144
4.5
168
3
12
2.5
240
tBu
100
100
100
80
OPiPr2
OP(OEt)2
PPh2
tBu
O
4a
5a
8a
6a
O
P
tBu
a
O
Ligand/Pd ratio¼1.5.
b
c
EtPPh2
P(OEt)3
tBu
MeOPCy2
Determined by NMR.
Determined by HPLC. The major product has S configuration.
O
P
O
MeO
Unfortunately full recovery of catalytic performance of the ionic
liquid solutions was not possible. In all cases the catalytic activity
was reduced, and as a consequence lower yields were obtained
(entries 8, 12, and 14) or much longer reaction times were required
for total conversion (entries 10 and 16). A drop in enantioselectivity
was also observed, with the only exception of 5b (entry 14), but
again the general trend was phosphite (4ae5a, 4e8% ee, entries 8
and 12)<phosphinite (6a, 32% ee, entry 16)<phosphane (8a, 54%
ee, entry 18).
Fig. 2. Model monodentate phosphines.
Attempts to crystallize the catalyst precursor 8a/Pd(allyl) were
unsuccessful. However the 1H NMR spectrum of this species (Fig. 4)
shows a total split of the signals of both oxazolines, one at higher
and the other one to lower field. This seems to indicate the co-
ordination of Pd to only one oxazoline ring, as well as to the
phosphane group, as shown by the 31P NMR chemical shift from
ꢀ23 ppm in 8a to 23 ppm in the complex. This result is in agree-
ment with the precedent with an NPN ligand based on oxazolines,19
in which the tridentate ligand acted as bidentate with the forma-
tion of a six-membered chelate. Ligands can only act as tridentate
when they are compatible with the planaresquare geometry of Pd,
3. Discussion
In the series of type a ligands, the bis(oxazoline) backbone is
identical in all cases, and only the phosphorous arm is changed. The

M.R. Castillo et al. / Tetrahedron 67 (2011) 5402e5408
5405
O
O
*
N
O
N
O
*
N
P
Pd
N
PPh2
Pd
P
Ph
Ph
O
Pd
ref. 19
Me
N
Ph
ref. 16c
8a-Pd
O
O
R
*
O
O
O
P
tBu
N
PPh2
N
ref. 47
N
Pd
ref. 46
Pd
P
Ph
Pd
Ph
ref. 40
Fig. 5. Possible NPNePd complexes, with the new stereogenic centers created, and the
simpler analogous NPePd complex.
Fig. 3. Relationship between enantiomeric ratio obtained in allylic substitution and P-
Pd bond distance in model compounds. Reactions in: (A) dichloromethane; (-)
[bmim][PF6]; (:) recovered in [bmim][PF6].
The loss of catalytic performance after recovery may be ascribed
to two different causes. On the one hand the partial extraction of
full complex due to its solubility in the extracting solvent or to the
existence of an equilibrium of complex formation, as already shown
in the case of bis(oxazoline)ecopper complexes in ionic liquids,48
allowing the extraction of free ligand, which in this case it is
highly detrimental for both catalytic activity and enantioselectivity
in the recovered ionic liquid phase. On the other hand the forma-
tion of Pd black particles is observed, which may also reduce the
concentration of active species. The correlation between the en-
antiomeric ratio obtained in the recovered ionic liquid phase and
the PePd bond distance (Fig. 3, r¼0.997) shows that the electronic
properties of the phosphorous group also control this aspect of
catalysis.
as in the case of pybox42 or pyridinebis(oxazolidines),43 whereas in
this case the tridentate ligand allows only the fac-coordination.
Analogous NON, NSN, and NNN tridentate ligands,13 including
tris(oxazolines),18 did not reach k3 coordination with Re, Fe, Cu, or
Pd, forming only the box chelate.
Studies about the coordination ability of this kind of ligands
with different metals, as well as the catalytic activity of the metal
complexes are currently under development.
4. Conclusion
Highly modular NPN ligands based on bis(oxazoline) skeleton
has been developed. Any type of phosphorous-containing group
can be introduced, including phophinite, phosphite or phos-
phane, with different possible substitutions (methyl and benzyl
have been used) at the methylene bridge between both oxazoline
rings.
Pd coordination seems to take place through the phosphorous-
containing group and one oxazoline ring, as the possible fac-co-
ordination cannot be reached with Pd. This type of ligands can be
more active and enantioselective than simpler analogues for allylic
substitution in dichloromethane, and it is able to promote the same
reaction in ionic liquids. The efficiency of the catalyst depends
mainly on the donor character of the phosphorous group, with
additional role of the substitution at the methylene bridge. Cata-
lysts are not fully recoverable in ionic liquids, showing that the
stability of the complex is a key issue to reach this goal.
Fig. 4. Comparison of the 1H NMR spectra of ligand 8a (top) and the 8aePd complex
(bottom).
With any of the ligands described in this work, PN chelation will
generate an additional stereogenic center on the quaternary carbon
at the bridge between the two oxazoline rings (Fig. 5). A similar
feature on phosphorous atom was produced in the previously de-
scribed NPN ligand (Fig. 5),19 or with the axial chirality in unfixed
biphenyl-phosphinooxazoline.16c The possible formation of di-
astereomers might account for the poorly resolved NMR signals
and the impossibility to crystallize the complex, although in the
other two mentioned cases Pd complexation led to only one of the
possible diastereomers. The importance of the presence of an ad-
ditional stereogenic center has been demonstrated by the match-
mismatch problem found with related phosphinooxazoline
ligands (Fig. 5),40 and the control of the absolute configuration of
the final product in phosphinooxazoline ligands with chiral back-
bone between the chelating groups, such as phosphanorborna-
diene,44 substituted ferrocene with planar chirality,45 P-stereogenic
atom,46 or 1,3-dioxolane47 (Fig. 5).
5. Experimental section
5.1. General methods
All manipulations were carried out with exclusion of air by using
standard Schlenk techniques or in an argon-filled MBraun drybox.
Solvents were obtained from
a Solvent Purification System
(MBraun). Deuterated solvents were dried with appropriate drying
agents and degassed with argon prior to use. CHN analyses were
carried out in a PerkineElmer 2400 CHNS/O analyzer. ESI MS were
obtained in a Bruker Microtof-Q mass spectrometer. Infrared

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M.R. Castillo et al. / Tetrahedron 67 (2011) 5402e5408
spectra were recorded in KBr using an FT-IR PerkineElmer Spec-
trum One spectrometer. NMR spectra were recorded in CDCl3 at rt
on Bruker Avance 500 or 400 MHz spectrometers. 1H (500.13 or
400.13 MHz) and 13C (125.8 or 100.6 MHz) NMR chemical shifts
were measured relative to the partially deuterated solvent peak but
are reported in parts per million relative to TMS. 31P (202.5 or
162.0 MHz) chemical shifts were measured relative to H3PO4 (85%).
Coupling constants, J, are given in hertz. In general, NMR spectral
assignments were achieved through 1H COSY, 1H NOESY, 13C APT,
1H/13C HSQC and 1H/13C HMBC experiments.
resulting solution was stirred for 3 days at rt. The solvent was
evaporated under reduced pressure, the crude was redissolved in
dichloromethane (5 ml), washed with water (3ꢂ4 ml), dried over
MgSO4, filtered and concentrated under vacuum. Yield: 838 mg
(75%). IR (n
cmꢀ1): 3237 (OeH), 1651 (C]N). Elemental analysis
(C15H26N2O3): theoretical C 63.80, H 9.28, N 9.92; experimental C
63.70, H 9.23, N 9.85. m/z (ESI): [MþH]þ¼283.1. 1H NMR: 4.23 (ABX,
dA¼3.85, dB¼3.80, dX¼4.60, JAB¼11.0, JAX¼6.4, JBX¼7.4; 3H; C(CH3)
CH2OH), 4.24e4.20 (m, 2H; CH2 oxazole), 4.02e3.92 (m, 4H; CH2
and CH oxazole), 1.81e1.69 (m, 2H; CHCH3), 1.44 (s, 3H; C(CH3)
CH2OH), 0.91 (d, J¼6.8, 3H; CHCH3), 0.90 (d, J¼6.8, 3H; CHCH3), 0.86
(d, J¼6.8, 3H; CHCH3), 0.85 (d, J¼6.8, 3H; CHCH3). 13C NMR: 167.30,
167.01 (2ꢂs, C]N), 71.44, 71.38 (2ꢂs, CH oxazole), 70.02, 69.95
(2ꢂs, CH2 oxazole), 67.71 (s, C(CH3)CH2OH), 44.28 (s, C(CH3)
CH2OH), 32.42, 32.31 (2ꢂs, CHCH3), 18.65 (s, C(CH3)CH2OH), 18.47,
18.33, 17.92, 17.79 (4ꢂs, CHCH3).
5.2. Synthesis of ligands
5.2.1. 2,20-Ethylidenebis[(4S)-4-isopropyl-4,5-dihydro-oxazole]
(2a). t-BuOK (480.7 mg, 4.2 mmol) was added to a solution of 2,20-
methylenebis[(4S)-4-isopropyl-4,5-dihydro-oxazole] (1) (1 g,
4.2 mmol) in THF (20 ml) at rt and the mixture was stirred for 1 h.
Methyl iodide (264.1
ml, 4.2 mmol) was added and the reaction was
5.2.4. 2,20-(1-Hydroxymethyl-2-phenylethylidene)bis[(4S)-4-
heated under reflux for 4 h. The solvent was evaporated under
reduced pressure, brine (15 ml) was added to the crude and the
aqueous phase was extracted with ethyl acetate (3ꢂ20 ml). The
combined organic phases were dried over MgSO4, filtered, and
concentrated under vacuum. Yield: 984 mg (93%) as a yellow oil. IR
isopropyl-4,5-dihydro-oxazole] (3b). From 2b (800 mg) following
the previous method. Yield: 733 mg (84%). IR (n
cmꢀ1): 3250 (OeH),
1647 (C]N). Elemental analysis (C21H30N2O3): theoretical C 70.36,
H 8.43, N 7.82; experimental C 70.44, H 8.45, N 7.89. m/z (ESI):
[MþH]þ¼358.9. 1H NMR: 7.27e7.22 (m, 5H; CHPh), 4.31e4.26
(m, 2H; CH2 oxazole, 1H; C(CH2Ph)CH2OH), 4.08 (m, 1H; CH2 oxa-
zole), 4.03e3.90 (m,1H; CH2 oxazole, 2H; CH oxazole, 2H; C(CH2Ph)
CH2OH), 3.31 (AB: dA¼3.33, dB¼3.29, JAB¼13.6, 2H; C(CH2Ph)
CH2OH), 1.78 (m, 1H; CHCH3), 1.67 (m, 1H; CHCH3), 0.96 (d, J¼6.7,
3H; CHCH3), 0.90 (d, J¼6.7, 3H; CHCH3), 0.89 (d, J¼6.7, 3H; CHCH3),
0.84 (d, J¼6.7, 3H; CHCH3). 13C NMR: 166.05, 166.04 (2ꢂs, C]N),
135.90 (s, CipsoePh), 130.47, 128.00, 126.78 (3ꢂs, Co-m-p-Ph), 71.72,
71.46 (2ꢂs, CH oxazole), 70.01, 69.80 (2ꢂs, CH2 oxazole), 64.67 (s,
C(CH2Ph)CH2OH), 48.93 (s, C(CH2Ph)CH2OH), 38.08 (s, C(CH2Ph)
CH2OH), 32.50, 32.38 (2ꢂs, CHCH3), 18.56 (s, 2C; CHCH3), 18.18,
17.94 (2ꢂs, CHCH3).
(n
cmꢀ1): 1608 (C]N). Elemental analysis (C14H24N2O2): theoretical
C 66.63, H 9.59, N 11.10: experimental C 66.72, H 9.57, N 11.18. m/z
(ESI): [MþH]þ¼253.1. 1H NMR: 4.20 (dd, J¼9.6, J¼8.0 Hz, 2H; CH2
oxazole), 3.96 (dd, J¼11.6, J¼7.6, 2H; CH2 oxazole), 3.93 (m, 2H; CH
oxazole), 3.50 (c, J¼7.2, 1H; CHCH3 ethylidene), 1.75 (m, 2H;
CHCH3), 1,45 (d, J¼7.2, 3H; CHCH3 ethylidene), 0.91 (d, J¼6.8, 3H;
CHCH3), 0.90 (d, J¼6.8, 3H; CHCH3), 0.83 (d, J¼6.8, 6H; CHCH3). 13
C
NMR: 165.52, 165.36 (2ꢂs, C]N), 71.75, 71.68 (2ꢂs, CH oxazole),
70.12, 70.07 (2ꢂs, CH2 oxazole), 33.94 (s, CHCH3 ethylidene), 32.29,
32.27 (2ꢂs, CHCH3), 18.59, 18.55, 17.69, 17.58 (4ꢂs, CHCH3), 15.27
(s, CHCH3 ethylidene).
5.2.2. 2,20-(2-Phenylethylidene)bis[(4S)-4-isopropyl-4,5-dihydro-ox-
azole] (2b). t-BuOK (240.4 mg, 2.1 mmol) was added to a solution
of 2,20-methylenebis[(4S)-4-isopropyl-4,5-dihydro-oxazole] (1)
(500 mg, 2.1 mmol) in THF (20 ml) at rt and the mixture was stirred
5.2.5. 2,20-(1-Bromomethylethylidene)bis[(4S)-4-isopropyl-4,5-
dihydro-oxazole] (7a). To a solution of 2a (1 g, 3.9 mmol) in THF
(20 ml) at ꢀ78 ꢁC was added n-BuLi (2.5 ml 1.6 M in hexanes,
4 mmol) and the mixture was stirred for 1 h. Then dibromo-
for 1 h. Benzyl bromide (254.8
ml, 2.1 mmol) was added and the
methane (278 ml, 3.9 mmol) was added and the reaction mixture
reaction was heated under reflux for 4 h. The solvent was evapo-
rated under reduced pressure, brine (15 ml) was added to the crude
and the aqueous phase was extracted with ethyl acetate (3ꢂ20 ml).
The combined organic phases were dried over MgSO4, filtered and
concentrated under vacuum. The yellow oil was purified by column
chromatography on neutral alumina (hexane/ethyl acetate¼65:35,
was heated under reflux for 4 h. The solvent was evaporated under
reduced pressure, brine (15 ml) was added to the crude and the
aqueous phase was extracted with ethyl acetate (3ꢂ20 ml). The
combined organic phases were dried over MgSO4, filtered, and
concentrated under vacuum. Yield: 1.24 g (94%) as a yellow oil. IR
(n
cmꢀ1): 1648 (C]N). Elemental analysis (C15H25N2O2Br): theo-
1% NEt3). Yield: 558 mg (81%). IR (
n
cmꢀ1): 1613 (C]N). Elemental
retical C 52.18, H 7.29, N 8.11; experimental C 52.08, H 7.20, N 8.21.
m/z (ESI): [MþH]þ¼345.1. 1H NMR: 4.24e4.18 (m, 2H; CH2 oxazole),
4.02e3.92 (m, 2H; CH2 oxazole, 2H; CH oxazole), 3.82 (AB: dA¼3.86,
dB¼3.83, JAB¼10.3, 2H; CCH3CH2Br), 1.83e1.74 (m, 2H; CHCH3), 1.61
(s, 3H; CCH3CH2Br), 0.91 (d, J¼7.0, 3H; CHCH3), 0.89 (d, J¼7.0, 3H;
analysis (C20H28N2O2): theoretical C 73.13, H 8.59, N 8.53; experi-
mental C 72.99, H 8.65, N 8.46. m/z (ESI): [MþH]þ¼329.1 1H NMR:
7.20e7.09 (m, 5H; CHPh), 4.15e4.13 (m, 2H; CH2 oxazole), 3.93e3.80
(m, 4H; CH2 and CH oxazole), 3.75e3.10 (ABX: dX¼3.71, dA¼3.22,
dB¼3.14, JAB¼13.6, JAX¼8.3, JBX¼8.7, 3H; CHCH2Ph), 1.65 (m, 1H;
CHCH3), 1.55 (m, 1H; CHCH3), 0.82 (d, J¼6.8, 3H; CHCH3), 0.75 (d,
J¼6.8, 3H; CHCH3), 0.73 (d, J¼6.8, 3H; CHCH3), 0.68 (d, J¼6.8, 3H;
CHCH3). 13C NMR: 163.86, 163.76 (2ꢂs, C]N), 138.07 (s, CipsoePh),
128.94, 128.20, 126.42 (3ꢂs, Co-m-p-Ph), 71.79, 71.77 (2ꢂs, CH oxa-
zole), 70.07, 70.02 (2ꢂs, CH2 oxazole), 41.24 (s, CHCH2Ph), 35.76
(s, CHCH2Ph), 32.29, 32.15 (2ꢂs, CHCH3), 18.51, 18.41, 17.72, 17.65
(4ꢂs, CHCH3).
CHCH3), 0.86 (d, J¼6.4, 3H; CHCH3), 0.84 (d, J¼6.4, 3H; CHCH3). 13
C
NMR: 165.40, 165.31 (2ꢂs, C]N), 71.93, 71.61 (2ꢂs, CH oxazole),
70.22, 70.10 (2ꢂs, CH2 oxazole), 43.47 (s, CCH3CH2Br), 37.42 (s,
CCH3CH2Br), 32.21, 32.16 (2ꢂs, CHCH3), 21.16 (s, CCH3CH2Br), 18.64,
18.44, 17.73, 17.45 (4ꢂs, CHCH3).
5.2.6. 2,20-[1-(Diethoxyphosphinooxymethyl)ethylidene]-bis[(4S)-4-
isopropyl-4,5-dihydro-oxazole] (4a). To a solution of 3a (360 mg,
ꢁ
1.27 mmol) in toluene (10 ml) was added 4 A molecular sieves and
5.2.3. 2,20-(1-Hydroxymethylethylidene)bis[(4S)-4-isopropyl-4,5-
the suspension was stirred for 8 h. The solution was transferred to
another Schlenk, 4-dimethylaminopyridine (171 mg, 1.40 mmol)
was added and stirred until complete dissolution. Chlor-
odiethylphosphite (220.6 ml, 1.46 mmol) was added dropwise and
the mixture was stirred for 18 h. The solution was filtered via
dihydro-oxazole] (3a). To
a stirred suspension of 2a (1 g,
3.96 mmol) and paraformaldehyde (148.5 mg, 4.95 mmol) in
dichloromethane (6 ml) were added 1,4-dioxane (1 ml) and water
(0.2 ml). A solution of NEt3 (0.8 ml) in THF (3 ml) was added
dropwise for 3 h and the solid was gradually dissolved. The
cannula, the resulting solution was evaporated under reduced

M.R. Castillo et al. / Tetrahedron 67 (2011) 5402e5408
5407
pressure, hexane was added to the crude and the solid was filtered
off. The final solution was concentrated under vacuum to obtain 4a
19.81 (s, C(CH3)CH2OP(OR)2), 18.49, 18.45, 17.45, 17.41 (4ꢂs,
CHCH3). 31P NMR: 135.15 (s).
as an oil Yield: 450 mg (87%). IR (n
cmꢀ1): 1649 (C]N). Elemental
analysis (C19H35N2O5P): theoretical C 56.70, H 8.76, N 6.96; exper-
imental C 56.63; H 8.81; N 6.92. m/z (ESI): [MþH]þ¼403.2. 1H NMR:
4.23e4.11 (m, 2H; C(CH3)CH2OP(OCH2CH3)2, 2H; CH2 oxazole),
3.99e3.91 (m, 2H; CH2 oxazole, 2H; CH oxazole), 3.88e3.81 (m, 4H;
OP(OCH2CH3)2), 1.81e1.73 (m, 2H; CHCH3 oxazole), 1.57 (s, 3H;
C(CH3)CH2OP(OEt)2), 1.23 (t, J¼7.0, 6H; OP(OCH2CH3)2), 0.90 (d,
J¼6.8, 3H; CHCH3), 0.89 (d, J¼6.6, 3H; CHCH3), 0.84 (d, J¼6.8, 3H;
CHCH3), 0.83 (d, J¼6.8, 3H; CHCH3). 13C NMR: 165.67, 166.65 (2ꢂs,
C]N), 71.85, 71.63 (2ꢂs, CH oxazole), 69.80, 69.61 (2ꢂs, CH2 oxa-
zole), 65.19 (d, J(CeP)¼11.4, C(CH3)CH2OP(OEt)2), 58.09 (d,
J(CeP)¼10.9, OP(OCH2CH3)2), 43.72 (d, J(CeP)¼5.5, C(CH3)CH2O-
P(OEt)2), 32.25, 32.15 (2ꢂs, CHCH3), 19.60 (s, C(CH3)CH2OP(OEt)2),
18.60, 18.51, 17.56, 17.35 (4ꢂs, CHCH3), 16.87 (d, J(CeP)¼4.9,
OP(OCH2CH3)2). 31P NMR: 138.87 (s).
5.2.9. (3,30,5,50-Tetra-tert-butyl-1,10-biphenyl-2,20-diyl)-{2,2-bis
[(4S)-4-isopropyl-4,5-dihydro-oxazol-2-yl]-3-phenyl-propyl}-phos-
phite (5b). From 3b (179 mg, 0.5 mmol) and (3,30,5,50-tetra-tert-
butyl-1,10-biphenyl-2,20-diyl)phosphorochloridite36 following the
previous procedure. Yield: 110 mg (28%). Elemental analysis
(C49H69N2O5P): theoretical C 73.84, H 8.73, N 3.52; experimental C
73.70, H 8.90, N 3.48. m/z (ESI): [MþH]þ¼797.5. 1H NMR: 7.45e7.43
(m, 2H; CHPh), 7.20e7.18 (m, 2H; CHPh), 7.15e7.09 (m, 5H; CHPh),
4.23 (ABX: dA¼4.26, dB¼4.21, JAB¼10.8, JAX¼6.0, JBX¼5.2; 2H;
C(CH2Ph)CH2OP(OR)2), 4.13 (m, 1H; CH2 oxazole), 4.05 (m, 1H; CH2
oxazole), 3.89 (m, 1H; CH2 oxazole), 3.87e3.78 (m, 2H; CH oxazole,
1H; CH2 oxazole), 3.40 (AB: dA¼3.42, dB¼3.35, JAB¼13.6, 2H;
C(CH2Ph)CH2OP(OR)2), 1.65 (m, 1H; CHCH3), 1.55 (m, 1H; CHCH3),
1.49 (s, 18H; C(CH3)3), 1.37(s, 18H; C(CH3)3), 0.83 (d, JHH¼6.0, 3H;
CHCH3), 0.80 (d, JHH¼6.0, 3H; CHCH3), 0.76 (d, JHH¼6.8, 3H; CHCH3),
0.75 (d, JHH¼6.8, 3H; CHCH3). 13C NMR: 164.05, 163.96 (2ꢂs, C]N),
146.47e124.21, 72.11, 71.99 (2ꢂs, CH oxazole), 69.86, 69.62 (2ꢂs,
CH2 oxazole), 63.74 (d, J(CeP)¼8.4; C(CH2Ph)CH2OP(OR)2), 48.47
(d, JCP¼5.3; C(CH2Ph)CH2OP(OR)2), 36.77 (C(CH2Ph)CH2OP(OR)2),
35.56, 35.55, 34.85 (3ꢂs, C(CH3)3), 32.54, 32.29 (2ꢂs, CHCH3), 31.75,
31.36, 31.29, 31.26, 31.25 (5ꢂs, C(CH3)3), 19.04, 18.83, 17.96, 17.79
(4ꢂs, CHCH3). 31P NMR: 145.3 (s).
5.2.7. 2,20-[1-(Diethoxyphosphinooxymethyl)-2-phenyl ethylidene]-
bis[(4S)-4-isopropyl-4,5-dihydro-oxazole] (4b). From 3b (240 mg,
0.67 mmol) following the previous procedure. Yield: 285 mg (89%).
IR (n
cmꢀ1): 1650 (C]N). Elemental analysis (C25H39N2O5P): the-
oretical C 62.74, H 8.21, N 5.85; experimental C 62.77, H 8.24, N 5.80.
m/z (ESI): [MþH]þ¼479.2. 1H NMR: 7.17e7.11 (m, 5H; CHPh),
4.17e4.08 (m, 2H; CH2 oxazole), 4.05 (ABX, dA¼4.09, dB¼4.00,
JAB¼10.8, JAX¼5.9, JBX¼5.4; 2H; C(CH2Ph)CH2OP(OEt)2), 3.92e3.80
(m, 2H; CH2 oxazole, 4H; OP(OCH2CH3)2, 2H; CH oxazole), 3.37 (AB:
dA¼3.40, dB¼3.35, JAB¼13.6, 2H; C(CH2Ph)CH2OP(OEt)2), 1.70 (m,
1H; CHCH3), 1.61 (m, 1H; CHCH3), 1.96 (t, J¼7.0, 6H; OP(OCH2CH3)2),
0.85 (d, J¼6.8, 3H; CHCH3), 0.78 (d, J¼6.6, 3H; CHCH3), 0.76 (d,
J¼6.8, 3H; CHCH3), 0.71 (d, J¼6.8, 3H; CHCH3). 13C NMR: 165.26,
164.20 (2ꢂs, C]N), 136.36 (s, CipsoePh), 130.49, 127.97, 126.60 (s, Co-
m-p-Ph), 72.14, 71.98 (2ꢂs, CH oxazole), 69.65, 69.46 (2ꢂs, CH2 oxa-
zole), 61.17 (d, J(CeP)¼12.8, C(CH2Ph)CH2OP(OEt)2), 58.09 (d,
J(CeP)¼10.5, OP(OCH2CH3)2), 58.00 (d, J(CeP)¼9.9, OP(OCH2CH3)2),
48.18 (d, J(CeP)¼6.3, C(CH2Ph)CH2OP(OEt)2), 36.21 (s, C(CH2Ph)
CH2OP(OEt)2), 32.36, 32.29 (2ꢂs, CHCH3), 18.79 18.70, 17.76,
17.61 (4ꢂs, CHCH3), 16.92 (d, J(CeP)¼4.8, OP(OCH2CH3)2). 31P NMR:
138.80 (s).
5.2.10. 2,20-[1-(Diisopropylphosphinooxymethyl)ethylidene]-bis
[(4S)-4-isopropyl-4,5-dihydro-oxazole] (6a). From 3a (785 mg,
2.78 mmol) and chlorodiisopropylphosphine following the pre-
vious procedure. Yield: 1.01 g (91%) as a pale yellow oil. IR (n
cmꢀ1):
1648 (C]N). Elemental analysis (C21H39N2O3P): theoretical C 63.29,
H 9.86, N 7.03; experimental C 63.25; H 9.92; N 6.99. m/z (ESI):
[MþH]þ¼399.2. 1H NMR: 4.19e4.13 (m, 2H; CH2 oxazole),
4.06e4.04 (m, 2H; C(CH3)CH2OPiPr2), 3.98e3.91 (m, 4H; CH2 and
CH oxazole), 1.81e1.73 (m, 2H; CHCH3), 1.72e1.63 (m, 2H; PCHCH3),
1.58 (s, 3H; C(CH3)CH2OPiPr2), 1.05 (dd, J(HeP)¼10.8, J(HeH)¼6.8, 3H;
PCHCH3), 1.04 (dd, J(HeP)¼10.8, J(HeH)¼6.0, 3H; PCHCH3), 1.00 (dd,
J(HeP)¼13.0, J(HeH)¼7.1, 3H; PCHCH3), 0.97 (dd, J(HeP)¼13.0,
J(HeH)¼7.4, 3H; PCHCH3), 0.90 (d, J¼6.8, 3H; CHCH3), 0.89 (d, J¼6.8,
3H; CHCH3), 0.83 (d, J¼6.8, 6H; CHCH3). 13C NMR: 165.84 (s, C]N),
74.40 (d, J(CeP)¼20.8, C(CH3)CH2OPiPr2), 71.82, 71.59 (2ꢂs, CH oxa-
zole), 69.67, 69.48 (2ꢂs, CH2 oxazole), 44.42 (d, J(CeP)¼9.6, C(CH3)
CH2OPiPr2), 32.28, 32.14 (2ꢂs, CHCH3), 28.10 (d, J(CeP)¼18.8,
PCHCH3), 27.94 (d, J(CeP)¼17.3, PCHCH3), 18.63, 18.56 (2ꢂs, CHCH3)
19.84 (s; C(CH3)CH2OPiPr2), 17.86 (d, J(CeP)¼5.9, PCHCH3), 17.64
(s, CHCH3), 17.29, 17.11, 17.02 (3ꢂs, PCHCH3). 31P NMR: 152.45 (s).
5.2.8. (3,30,5,50-Tetra-tert-butyl-1,10-biphenyl-2,20-diyl)-{2,2-bis
[(4S)-4-isopropyl-4,5-dihydro-oxazol-2-yl]propyl}-phosphite (5a). A
solution of 3a (142 mg, 0.5 mmol) and dimethylaminopyridine
(0.5 mmol, 61 mg, azeotropically pre-dried over toluene
(3ꢂ1 mL)), in dry degassed toluene (10 mL) and cooled to 0 ꢁC,
was slowly added to a solution of (3,30,5,50-tetra-tert-butyl-1,10-
biphenyl-2,20-diyl)phosphorochloridite36 (0.6 mmol, 285 mg) in
dry degassed toluene (2 mL). The mixture was allowed to warm to
rt and stirred overnight. The mixture was then filtered to eliminate
the pyridine salts, and the filtrate was concentrated to dryness.
The white foam obtained was purified by flash chromatography
over nitrogen. Yield: 100 mg (28%). Elemental analysis
(C43H65N2O5P): theoretical C 71.64, H 9.09, N 3.89; experimental C
71.60, H 9.20, N 3.87. m/z (ESI): [MþH]þ¼721.4. 1H NMR: 7.42e7.41
(m, 2H; CHPh), 7.17e7.16 (m, 2H; CHPh), 4.13e4.02 (m, 2H; C(CH3)
CH2OP(OR)2, 2H; CH2 oxazole), 3.94e3.84 (m, 2H; CH2 oxazole,
2H; CH oxazole), 1.75e1.68 (m, 2H; CHCH3), 1.53 (s, 3H; C(CH3)
CH2OP(OR)2), 1.48 (s, 18H; C(CH3)3), 1.34 (s, 18H, C(CH3)3), 0.85
(d, JHH¼6.8, 3H; CHCH3), 0.84 (d, JHH¼6.8, 3H; CHCH3), 0.79
(d, JHH¼6.8, 6H; CHCH3). 13C NMR: 165.33, 166.32 (2ꢂs, C]N),
146.35 (d, JCP¼4.0; Cipso-OP), 139.73 (d, JCP¼2.7; Cipsoet-Bu), 132.66
(d, JCP¼1.2; CipsoeCipso), 132.63 (d, JCP¼1.2; Cipsoet-Bu), 126.49,
124.15 (2ꢂs, CHPh), 71.61, 71.51 (2ꢂs, CH oxazole), 69.60 (s, CH2
oxazole), 66.11 (s, C(CH3)CH2OP(OR)2), 43.65 (d, JCP¼4.3; C(CH3)
CH2OP(OR)2), 35.29, 35.26, 34.60 (3ꢂs, C(CH3)3), 32.13, 31.99 (2ꢂs,
CHCH3 oxazole), 31.48, 30.92, 30.90, 30.86, 30.83 (5ꢂs, C(CH3)3),
5.2.11. 2,20-[1-(Diphenylphosphinomethyl)ethylidene]-bis [(4S)-4-
isopropyl-4,5-dihydro-oxazole] (8a). To
a solution of 7a (1 g,
3.9 mmol) in THF (20 ml) at 0 ꢁC KPPh2 (2.5 ml, 4 mmol) was added
and the mixture was stirred for 1 h. The solvent was evaporated
under reduced pressure, toluene (20 ml) was added to the crude
and the solid was filtered off. The resulting solution was evaporated
under reduced pressure, and the solid obtained was repeatedly
washed with hexane. Yield: 587 mg (45%) as white solid. IR
(n
cmꢀ1): 1655 (C]N). Elemental analysis (C27H35N2O2P): theo-
retical C 71.97, H 7.83, N 6.21; experimental C 72.78; H 8.14; N 5.86.
m/z (ESI): [MþH]þ¼451.2. 1H NMR: 7.50e7.44 (m, 4H; CHoePh),
7.32e7.27 (m, 6H; CHm-p-Ph), 4.10 (m, 1H; CH2 oxazole), 3.89e3.77
(m, 2H; CH2 oxazole, 1H; CH oxazole, 1H; CH2 oxazole, 1H; CH
oxazole), 3.83 (ABX: dA¼2.87, dB¼2.79, JAB¼14.2, JAX¼4.0, JBX¼3.1,
2H, CCH3CH2PPh2), 1.77 (m, 1H; CHCH3), 1.69 (m, 1H; CHCH3), 1.60
(s, 3H, CCH3CH2PPh2), 0.92 (d, J¼6.8, 3H; CHCH3), 0.88 (d, J¼6.8, 3H;
CHCH3), 0.82 (d, J¼6.8, 6H; CHCH3), 0.81 (d, J¼6.8, 6H; CHCH3). 13
C
NMR: 167.89 (d, JCP¼5.5, C]N), 167.53 (d, JCP¼4.5, C]N), 139.44
(d, JCP¼4.1, CipsoePh), 139.26 (d, JCP¼5.0, CipsoePh), 133.40 (d, JCP¼20.1,

5408
M.R. Castillo et al. / Tetrahedron 67 (2011) 5402e5408
ꢀ
7. Gomez, M.; Jansat, S.; Muller, G.; Maestro, M. A.; Mahía, J. Organometallics 2002,
C
C
o-Ph), 132.81 (d, JCP¼19.3, Co-Ph), 128.46 (s, Cp-Ph), 128.27 (d, JCP¼6.4,
21, 1077.
m-Ph), 128.23 (s, Cp-Ph), 128.22 (d, JCP¼6.8, Cm-Ph), 71.95, 71.51 (2ꢂs,
8. Voituriez, A.; Fiaud, J.-C.; Schulz, E. Tetrahedron Lett. 2002, 43, 4907.
9. Nishiyama, H. Chem. Soc. Rev. 2007, 36, 1133.
10. Jiang, Y.; Jiang, Q.; Zhu, G.; Zhang, X. Tetrahedron Lett. 1997, 38, 215.
11. Braunstein, P.; Naud, F.; Pfaltz, A.; Rettig, S. J. Organometallics 2000, 19, 2676.
12. (a) Zhou, J.; Tang, Y. Chem. Soc. Rev. 2005, 34, 664; (b) Gade, L. H.; Bellemin-
Laponnaz, S. Chem.dEur. J. 2008, 14, 4142.
13. (a) Zhou, J.; Ye, M.-C.; Tang, Y. J. Comb. Chem. 2004, 6, 301; (b) Bichler, P.; Sun, A.
D.; Patrick, B. O.; Love, J. A. Inorg. Chim. Acta 2009, 362, 4546.
14. Tsuji, J. Palladium Reagents and Catalysts: New Perspectives for the 21st Century;
John Wiley: Chichester, UK, 2004, pp 432e518.
CH oxazole), 70.15, 69.67 (2ꢂs, CH2 oxazole), 41.99 (d, JCP¼20.6,
CCH3CH2PPh2), 37.35 (d, JCP¼16.8, CCH3CH2PPh2), 32.43, 32.13 (2ꢂs,
CHCH3), 23.06 (d, JCP¼12.6, CCH3CH2PPh2), 18.85, 18.65, 17.83, 17.39
(4ꢂs, CHCH3). 31P NMR: ꢀ23.06 (s).
5.3. Catalytic reactions
15. (a) Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258; (b) Trost, B. M. J. Org. Chem.
2004, 69, 5813; (c) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921;
(d) Trost, B. M.; Machacek, M. L.; Aponick, A. Acc. Chem. Res. 2006, 39, 747.
16. Some recent examples: (a) Wang, Y.; Hamalainen, A.; Tois, J.; Franzen, R. Tet-
rahedron: Asymmetry 2010, 21, 2376; (b) Grabulosa, A.; Muller, G.; Ceder, R.;
Maestro, M. A. Eur. J. Inorg. Chem. 2010, 3372; (c) Tian, F.; Yao, D.; Zhang, Y. J.;
Zhang, W. Tetrahedron 2009, 65, 9609.
5.3.1. Allylic substitution in dichloromethane. To a solution of the
chiral ligand (0.029 mmol) in anhydrous dichloromethane (2 ml),
was added [{PdCl(h-C3H5)}2] (3.5 mg, 0.0096 mmol). The resulting
mixture was deoxygenated and stirred for 2 h at rt. To this solution
€
€ €
ꢀ
were sequentially added rac-(E)-1,3-diphenylprop-2-enyl acetate
(126.05 mg, 0.5 mmol), diethyl malonate (164.1
ml, 1.07 mmol), N,O-
17. Chelucci, C.; Deriu, S.; Pinna, G. A.; Saba, A.; Valenti, R. Tetrahedron: Asymmetry
1999, 10, 3803.
bis(trimethylsilyl)acetamide (BSA, 352.1 l, 1.44 mmol) and sodium
m
18. Foltz, C.; Enders, M.; Bellemin-Laponnaz, S.; Wadepohl, H.; Gade, L. H. Chem.
dEur. J. 2007, 13, 5994.
19. Yamagishi, T.; Onuki, M.; Kiyooka, T.; Msuu, D.; Sato, K.; Yamaguchi, M. Tetra-
hedron: Asymmetry 2003, 14, 3275.
20. (a) Gamez, P.; Dunjic, B.; Fache, F.; Lemaire, M. Tetrahedron: Asymmetry 1995, 6,
1109; (b) Hallman, K.; Macedo, E.; Nordstrom, K.; Moberg, C. Tetrahedron:
Asymmetry 1999, 10, 4037; (c) Hallman, K.; Moberg, C. Tetrahedron: Asymmetry
2001, 12, 1475.
21. (a) Song, C. E.; Yang, J. W.; Roh, E. J.; Lee, S. G.; Ahn, J. H.; Han, H. Y. Angew. Chem.,
Int. Ed. 2002, 41, 3852; (b) Belda, O.; Lundgren, S.; Moberg, C. Org. Lett. 2003, 5,
2275.
22. (a) Shibatoni, K.; Uozumi, Y. Tetrahedron: Asymmetry 2002, 13, 1769; (b)
Uozumi, Y.; Shibatomi, K. J. Am. Chem. Soc. 2001, 123, 2919; (c) Uozumi, Y.;
Tanaka, H.; Shibatomi, K. Org. Lett. 2004, 6, 281; (d) Uozumi, Y.; Kimura, M.
Tetrahedron: Asymmetry 2006, 17, 161; (e) Uozumi, Y.; Suzuka, T. J. Org. Chem.
2006, 71, 8644.
acetate (small amount), and the mixture was again deoxygenated.
The reaction was monitored bygas chromatography (HP 5890 Series
II, FID, HP-1 column 30mꢂ0.25 mmꢂ0.25
mm; 20 psi helium, oven
temperature program: 50 ꢁC (1 min), 20 ꢁC/min, 270 ꢁC (5 min);
retention times: substrate 11.2 min, product 13.2 min). At the end of
the reaction, the solution was diluted with diethyl ether, washed
with saturated aqueous solution of NH4Cl, dried over MgSO4, and
evaporated at reduced pressure. The crude was purified by flash
chromatography. The enantiomeric excess was determined by HPLC
(Waters Alliance 2695, PDA 2996, ChiralPak AD-H 0.46 cmꢂ25 cm,
hexane/iPrOH (90/10) 1 ml/min, retention times: substrate 5.9 and
6.2 min, (R)-product 10.1 min (S)-product 13.7 min).
23. Bayardon, J.; Sinou, D. Tetrahedron: Asymmetry 2005, 16, 2965.
24. Hashizume, T.; Yonehara, K.; Ohe, K.; Uemara, S. J.Org. Chem. 2000, 65, 5197.
25. Dupont, J.; de Souza, R. F.; Suarez, P. A. Z. Chem. Rev. 2002, 102, 3667.
26. (a) Ross, J.; Chen, W.; Xu, L.; Xiao, J. Organometallics 2001, 20, 138; (b) Liao, M.;
Duan, X.; Liang, Y. Tetrahedron Lett. 2005, 46, 3469; (c) Hubert, C.; Renaud, J.-L.;
Demerseman, B.; Fischmeister, C.; Bruneau, C. J. Mol. Catal. A 2005, 237, 161.
5.3.2. Allylic substitution in [bmim][PF6]. To a solution of the chiral
ligand (0.029 mmol) in [bmim][PF6] (0.5 ml pre-dried under vac-
uum in the presence of P2O5) was added [{PdCl(h-C3H5)}2] (3.5 mg,
0.0096 mmol). The resulting mixture is deoxygenated and stirred
for 2 h at rt. To this solution were sequentially added rac-(E)-1,3-
diphenylprop-2-enyl acetate (126.05 mg, 0.5 mmol), diethyl mal-
ꢀ
ꢂꢀ
ꢀ
27. (a) Toma, S.; Gotov, B.; Kmentova, I.; Solcaniova, E. Green Chem. 2000, 2, 149;
ꢀ
ꢀ
ꢀ
(b) Kmentova, I.; Gotov, B.; Solcaniova, E.; Toma, S. Green Chem. 2002, 4, 103.
28. von Matt, P.; Lloydjones, G. C.; Minidis, A. B. E.; Pfaltz, A.; Macko, L.; Neubuger,
M.; Zehnder, M.; Ruegger, H.; Pregosin, P. S. Helv. Chim. Acta 1995, 78, 265.
29. Glos, M.; Reiser, O. Org. Lett. 2000, 2, 2045.
onate (164.1
ml, 1.07 mmol), N,O-bis(trimethylsilyl)acetamide (BSA,
352.1 l, 1.44 mmol) and sodium acetate (small amount), and the
m
ꢀ
30. Perez, I. Ph.D. Dissertation, University of Zaragoza, 2008.
31. Chen, W.; Xu, L.; Chatterton, C.; Xiao, J. Chem. Commun. 1999, 1247.
32. Aggarwal, V. K.; Bell, L.; Coogan, M. P.; Jubault, P. J. Chem. Soc., Perkin Trans.
1 1998, 2037.
mixture was again deoxygenated. At the end of the reaction, the
products were extracted with hexane, and treated and analyzed as
described before.
33. Burguete, M. I.; Fraile, J. M.; García, J. I.; García-Verdugo, E.; Luis, S. V.; Mayoral,
J. A. Org. Lett. 2000, 2, 3905.
34. Rechavi, D.; Lemaire, M. Org. Lett. 2001, 3, 2493.
35. (a) Mata, Y.; Dieguez, M.; Pamies, O.; Claver, C. Adv. Synth. Catal. 2005, 347,
Acknowledgements
ꢀ
ꢃ
ꢃ
ꢀ
1943; (b) Pamies, O.; Dieguez, M.; Claver, C. J. Am. Chem. Soc. 2005, 127, 3646;
ꢀ
ꢃ
(c) Mata, Y.; Dieguez, M.; Pamies, O.; Claver, C. Adv. Synth. Catal. 2008, 350,
2583; (d) Mata, Y.; Dieguez, M.; Pamies, O.; Claver, C. Adv. Synth. Catal. 2009,
351, 3217.
This research was supported by the Ministerio de Ciencia e
ꢀ
ꢃ
ꢀ
Innovacion (projects CTQ2009-08023, CTQ2008-05138 and Con-
solider Ingenio 2010 INTECAT CSD2006-0003).
36. Buisman, G. J. H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. Tetrahedron: Asym-
metry 1993, 4, 1625.
37. Sprinz, J.; Helmchen, G. Tetrahedron Lett. 1993, 34, 1769.
38. Selvakumar, K.; Valentini, M.; Pregosin, P. S.; Albinati, A.; Eisentrager, F. Or-
Supplementary data
€
ganometallics 2000, 19, 1299.
ꢀ
ꢀ
39. Franco, D.; Gomez, M.; Jimenez, F.; Muller, G.; Rocamora, M.; Maestro, M. A.;
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.05.079.
Mahía, J. Organometallics 2004, 23, 3197.
40. Gilbertson, S. R.; Chang, C.-W. T. J. Org. Chem. 1998, 63, 8424.
41. Jover, J.; Fey, N.; Harvey, J. N.; Lloyd-Jones, G. C.; Orpen, A. G.; Owen-Smith, G. J. J.;
Murray, P.; Hose, D. R. J.; Osborne, R.; Purdie, M. Organometallics 2010, 29, 6245.
References and notes
€
€
42. Nesper, R.; Pregosin, P.; Puntener, K.; Worle, M.; Albinati, A. J. Organomet. Chem.
1996, 507, 85.
43. Strong, E. T. J.; Cardile, S. A.; Brazeau, A. L.; Jennings, M. C.; McDonald, R.; Jones,
N. D. Inorg. Chem. 2008, 47, 10575.
44. Gilbertson, S. R.; Genov, D. G.; Rheingold, A. L. Org. Lett. 2000, 2, 2885.
45. Deng, W.-P.; You, S.-L.; Hou, X.-L.; Dai, L.-X.; Yu, Y.-H.; Xia, W.; Sun, J. J. Am.
Chem. Soc. 2001, 123, 6508.
46. Danjo, H.; Higuchi, M.; Yada, M.; Imamoto, T. Tetrahedron Lett. 2004, 45, 603.
47. Trudau, S.; Morken, J. P. Tetrahedron 2006, 62, 11470.
48. Fraile, J. M.; García, J. I.; Herrerías, C. I.; Mayoral, J. A.; Reiser, O.; Vaultier, M.
Tetrahedron Lett. 2004, 45, 6765.
1. Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2006, 106, 3561.
2. (a) McManus, H. A.; Guiry, P. J. Chem. Rev. 2004, 104, 4151; (b) Hargaden, G. C.;
Guiry, P. J. Chem. Rev. 2009, 109, 2505.
3. Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336.
4. Desimoni, G.; Faita, G.; Quadrelli, P. Chem. Rev. 2003, 103, 3119.
5. (a) Lu, S.-F.; Du, D.-M.; Zhang, S.-W.; Xu, J. Tetrahedron: Asymmetry 2004, 15,
3433; (b) Lu, S.-F.; Du, D.-M.; Xu, J.; Zhang, S.-W. J. Am. Chem. Soc. 2006, 128,
7418.
6. Inoue, M.; Suzuki, T.; Nakada, M. J. Am. Chem. Soc. 2003, 125, 1140.