Chiral phosphite-oxazolines: A new class of ligands for asymmetric Heck reactions

Article abstract of DOI:10.1021/ol052176h

(Chemical Equation Presented) A series of phosphite-oxazoline ligands, derived from readily available D-glucosamine, have been used for the first time in the palladium-catalyzed Heck reaction of several substrates with high regio- and enantioselectivities (ee's up to 99%) and improved activities in standard conditions.

Full text of DOI:10.1021/ol052176h

ORGANIC
LETTERS
2
005
Vol. 7, No. 25
597-5599
Chiral Phosphite-oxazolines: A New
Class of Ligands for Asymmetric Heck
Reactions
5
Yvette Mata, Montserrat Di e´ guez,* Oscar P a` mies,* and Carmen Claver
Departament de Qu ´ı mica F ´ı sica i Inorg a` nica, UniVersitat RoVira i Virgili, C/Marcel‚li
Domingo, s/n, 43007 Tarragona, Spain
montserrat.dieguez@urV.net; oscar.pamies@urV.net
Received September 9, 2005
ABSTRACT
A series of phosphite-oxazoline ligands, derived from readily available D-glucosamine, have been used for the first time in the palladium-
catalyzed Heck reaction of several substrates with high regio- and enantioselectivities (ee’s up to 99%) and improved activities in standard
conditions.
One of the main objectives in modern synthetic organic
chemistry is the catalytic enantioselective formation of C-C
bonds. In this respect, the asymmetric Pd-catalyzed Heck
reaction coupling of an aryl or alkenyl halide or triflate to
an alkene is a powerful and highly versatile procedure
In the past few years, a class of heterodonor ligands, the
phosphine-oxazolines, have emerged as suitable ligands for
the intermolecular Heck reaction. Despite this success, the
ligands that provide good regio- and enantioselectivities
usually have two important drawbacks: (1) the reaction times
are usually long and (2) they are prepared from expensive
chiral synthons. Thus, the development of ligands that induce
higher rates and enantioselectivitities in this reaction is of
great importance.
2
1
because it tolerates several functional groups. Chiral biden-
tate phosphine ligands have played a key role in the success
of this process. However, in the intermolecular Heck reaction,
the regioselectivity is often a problem. So, for example, in
the Heck reaction of 2,3-dihydrofuran 1 with phenyl triflate,
a mixture of two products is obtained: the expected product
For this purpose, carbohydrates are particularly advanta-
geous thanks to their low price and easy modular construc-
tions. Although they have been successfully used in other
2-phenyl-2,5-dihydrofuran 2 and 2-phenyl-2,3-dihydrofuran
3
3
(Scheme 1). The latter is formed by an isomerization
enantioselective reactions, there are only two reports on the
1
process.
highly enantioselective palladium-catalyzed asymmetric Heck
4
reaction using these types of ligands. In recent years,
(1) For recent reviews, see: (a) Tietze, L. T.; Ila, H.; Bell, H. P. Chem
ReV. 2004, 104, 3453. (b) Dai, L. X.; Tu, T.; You, S. L.; Deng, W. P.;
Hou, X. L. Acc. Chem. Res. 2003, 36, 659. (c) Bolm, C.; Hildebrand, J. P.;
Mu n˜ iz, K.; Hermanns, N. Angew. Chem., Int. Ed. 2001, 44, 3284. (d)
Shibasaki, M.; Vogl E. M. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Heidelberg,
Scheme 1
1
999. (e) Loiseleur, O.; Hayashi, M.; Keenan, M.; Schemees, N.; Pfaltz,
A. J. Organomet. Chem. 1999, 576, 16. (f) Beller, M.; Riermeier, T. H.;
Stark G. In Transition Metals for Organic Synthesis; Beller, M., Bolm, C.,
Eds.; Wiley-VCH: Weinheim, 1998.
1
0.1021/ol052176h CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/12/2005

phosphite ligands have emerged as suitable ligands for many
metal-catalyzed asymmetric processes. Phosphite ligands are
To the best of our knowledge, this is the first example of
phosphite-oxazoline ligands applied to the Heck reaction.
The synthesis of ligands 4-6 is straightforward (Scheme
5
extremely attractive for catalysis because they are easy to
prepare from readily available alcohols. The availability of
many alcohols makes simple ligand-tuning possible, which
allows the synthesis of many series of chiral ligands that
can be screened for high activity and selectivity. Taking
advantage of this high modularity and following our interest
in carbohydrates as highly versatile and cheap raw materials,
in this paper we describe a new family of phosphite-oxazoline
ligands (Scheme 2) derived from natural D-glucosamine, for
7
2). They are easily prepared by attaching several phospho-
8
9
rochloridites to the hydroxy-oxazoline scaffolds. The highly
modular construction of these ligands enables us to easily
study the effects of both the phosphite and the oxazoline
moieties on catalytic activity and selectivity. By carefully
selecting these elements we achieved high regio- and
enantioselectivities and improved activities for several
substrates.
For an initial evaluation of this new type of ligand for the
palladium-catalyzed asymmetric Heck reaction, we chose the
phenylation of 2,3-dihydrofuran 1 (Scheme 1). As this
reaction has been carried out with a variety of ligands
carrying different donor groups, it is possible to directly
compare the efficacy of different ligand systems. The
reactions were carried out with the palladium complex
generated in situ by mixing the corresponding chiral ligand
Scheme 2
1
0
2 3
and [Pd (dba) ]‚dba.
In a first set of experiments, we used ligand 4 to investigate
how the solvent and temperature affected the activity and
selectivity of the catalyst (Table 1, entries 1-6). In all cases,
Table 1. Pd-Catalyzed Enantioselective Phenylation of
a
2,3-Dihydrofuran 1 Using Phosphite-oxazoline Ligands 4-9
entry
ligand
solvent
% conv (2:3)b
% ee 2c
% ee 3c
1
2
3
4
5
6
7
8
9
1
4
4
4
4
4
4
5
6
7
8
9
toluene
benzene
DMF
THF
THF
THF
THF
THF
THF
THF
80 (85:15)
77 (84:16)
15 (71:29)
98 (87:13)
100 (80:20)
28 (88:12)
80 (71:29)
12 (65:35)
86 (85:15)
45 (60:40)
100 (97:3)
96 (R)
95 (R)
87 (R)
97 (R)
93 (R)
98 (R)
84 (R)
83 (R)
97 (R)
80 (R)
99 (R)
70 (R)
60 (R)
nd
88 (R)
87 (R)
88 (R)
90 (R)
23 (R)
89 (R)
69 (R)
nd
d
e
0
f,g
the highly selective Pd-catalyzed Heck reactions. These
ligands provide a highly flexible ligand scaffold because they
can be easily tuned in two different regions (phosphite and
oxazoline substituents) to explore how they affect the
catalytic performance. In addition, the presence of a phos-
phite moiety is advantageous because the larger π-acceptor
11
THF
a
-2
[
Pd2(dba)3]‚dba (1.25 × 10 mmol), 1 (2.0 mmol), phenyl triflate (0.5
-
2
i
mmol), ligand (2.8 × 10 mmol), solvent (3 mL), Pr2NEt (1 mmol), T )
b
c
5
0 °C, t ) 24 h. Conversion percentages determined by GC. Enantio-
meric excesses measured by GC. T ) 75 °C. e T ) 25 °C, t ) 67 h. f t )
5 h. g Isolated yield of 2 was 86%.
d
1
6
ability of the phosphite moiety increases the reaction rates.
the formation of the expected product 2-phenyl-2,5-dihy-
drofuran 2 was favored toward the formation of 2-phenyl-
2,3-dihydrofuran 3.
Our results indicated that the solvent and the temperature
each affect both the activity and selectivity of the process.
The optimum tradeoff between activities and selectivities was
obtained using THF as solvent and a temperature of 50 °C.
(2) See for instance: (a) Loiseleur, O.; Meier, P.; Pfaltz, A. Angew.
Chem., Int. Ed. Engl. 1996, 35, 200. (b) Loiseleur, O.; Hayashi, M.;
Schmees, N.; Pfaltz, A. Synthesis 1997, 1338. (c) Tu, T.; Hou, X. L.; Dai,
L. X. Org. Lett. 2003, 5, 3651. (d) Gilbertson, S. R.; Xie, D.; Fu, Z. J.
Org. Chem. 2001, 66, 7240. (e) Gilbertson, S. R.; Fu, Z. Org. Lett. 2001,
3
, 161.
3) Di e´ guez, M.; P a` mies, O.; Claver, C. Chem. ReV. 2004, 104, 3189.
b) Di e´ guez, M.; P a` mies, O.; Ruiz, A.; D ´ı az, Y.; Castill o´ n, S.; Claver, C.
(
(
Coord. Chem. ReV. 2004, 248, 2165. (c) Di e´ guez, M.; Ruiz, A.; Claver, C.
Dalton Trans. 2003, 2957. (d) P a` mies, O.; Di e´ guez, M.; Ruiz, A.; Claver,
C. Chem. Today 2004, 12.
(6) van Strijdonck, G. P. F.; Boele, M. D. K.; Kamer, P. C. J.; de Vries,
J. G.; van Leeuwen, P. W. N. M. Eur. J. Inorg. Chem. 1999, 1073.
(7) Mata, Y.; Di e´ guez, M.; P a` mies, O.; Claver, C. AdV. Synth. Catal. In
press.
(8) Phosphorochloridites are easily prepared in one step from the
corresponding bisphenol as described in Buisman, G. J. H.; Kamer, P. C.
J.; van Leeuwen, P. W. N. M. Tetrahedron: Asymmetry 1993, 4, 1625.
(9) Yonehara, K.; Hashizume, T.; Mori, K.; Ohe, K.; Uemura, S. J. Org.
Chem. 1999, 64, 9374.
(4) (a) Yonehara, K.; Mori, K.; Hashizume, T.; Chung, K. G.; Ohe, K.;
Uemura, S. J. Organomet. Chem. 2000, 603, 40. (b) Imbos, R.; Minnaard,
A. J.; Feringa, B. L. J. Am. Chem. Soc. 2002, 124, 184.
(5) See for instance: (a) Di e´ guez, M.; P a` mies O.; Claver, C. Tetrahe-
dron: Asymmetry 2004, 15, 2113. (b) Di e´ guez, M.; P a` mies, O.; Ruiz, A.;
Claver, C. In Methodologies in Asymmetric Catalysis; American Chemical
Society: Washington, DC, 2004; Chapter 11 and references therein.
5598
Org. Lett., Vol. 7, No. 25, 2005

The other ligands were compared under standard condi-
tions (THF, 24 h, and T ) 50 °C).
Scheme 3
Ligands 5 and 6, whose substituents in the oxazoline
moiety are different from that of ligand 4, showed lower
activities and lower regio- and enantioselectivities than ligand
4
(Table 1, entries 7 and 8 vs 4). We thus observed that
when the size of the group on the oxazoline increases, the
activity, regio- and enantioselectivity of the catalyst decreases
i
t
(
i.e., Ph > Pr > Bu). This contrasts with the oxazoline-
substituent effect observed for phosphine-oxazoline PHOX
ligands, whose enantioselectivites are higher when bulky tert-
butyl groups are present.2
a,b
The use of ligands 4 and 7-9 showed that the phosphite
moiety had an important effect on the activities and selectivi-
ties of the process. Ligand 7, with methoxy groups instead
of the tert-butyl groups in the para positions of the biphenyl
moieties, produced slightly lower regioselectivity and lower
activities than the catalytic system Pd/4 (Table 1, entry 9 vs
4
). Ligand 8, with a unsubstituted biphenyl moiety, provided
much lower activity and selectivity (regio- and enantiose-
lectivity) (Table 1, entry 10). The use of ligand 9, with SiMe
high enantioselectivity (92%) and good activity. These results
compete favorably with the best ligands developed for these
substrates.
3
groups in the ortho position of the biphenyl moiety, showed
excellent regio- and enantioselectivities combined with high
activity (Table 1, entry 11).
Our results clearly show that activities, regioselectivities,
and enantiomeric excesses depended strongly on both the
phosphite and oxazoline substituents. Therefore, the best
regio- and enantioselectivities were obtained using ligand
1
In summary, we have described the first application of
phosphite-oxazoline ligands in asymmetric Heck reactions.
These ligands can be prepared in a few steps from com-
mercial D-glucosamine as an inexpensive natural chiral
source. We found that the degree of isomerization and the
effectiveness in transferring the chiral information in the
product and the activity can be tuned by suitable choice of
the ligand components (phosphite and oxazoline substitu-
ents). These ligands compete favorably with the most
9, containing trimethylsilyl groups at the ortho positions of
the biphenyl phosphite moiety and a phenyl substituent in
the oxazoline. This result is among the best reported for this
type of substrate.1
1
successful ligands developed for this reaction. Note also that
To further study the potential of these modular and readily
available ligands, we subsequently applied them in the Pd-
catalyzed Heck reaction of other substrates and another
triflate (Scheme 3). The best results were obtained with
ligand 4, which contains bulky substituents at the ortho and
para positions of the biphenyl phosphite moiety and a phenyl
substituent in the oxazoline.
Reaction of dihydrofuran 1 and 1-cyclohexenyl triflate
gave an excellent result, with the coupling product 10
observed with 98% ee in high regioselectivity (98%) and
activity (100% conversion in 18 h). Reaction of cyclopentene
these ligands provided higher activities than those for other
successful ligands. These facts together with the low cost of
the ligands make these catalyst systems highly attractive for
further research. These results open up a new class of ligands
for the enantioselective Pd-catalyzed Heck reaction, which
will be of great practical interest. For example, phosphites
are less sensitive to oxidation than phosphines. Moreover,
because of the modular construction of phosphite-oxazoline
ligands, structural diversity is easy to achieve, so activities
and regio- and enantioselectivity can be maximized for each
new substrate as required.
1
1
1 and phenyl triflate at 70 °C gave the coupling product
2 with 94% ee in 100% conversion, together with small
Acknowledgment. This work was supported by the
Spanish Ministerio de Educaci o´ n, Cultura y Deporte
(BQU2001-0656), the Spanish Ministerio de Ciencia y
Tecnologia (Ramon y Cajal fellowship to O.P.) and the
Generalitat de Catalunya (Distinction to M.D.).
amounts of achiral 4-phenylcyclopentene. Reaction of phenyl
triflate and 4,7-dihydro-1,3-dioxepin 13 also proceeded with
-
2
(
10) Typical Procedure. A mixture of [Pd2(dba)3]dba (1.25 × 10
-2
mmol) and the chiral ligand (2.8 × 10 mmol) in dry degassed solvent
(
3.0 mL) was stirred under argon at room temperature for 15 min. The
Supporting Information Available: 1H and 13C NMR
spectra and elemental analysis for compounds 4-9. This
material is available free of charge via the Internet at
http://pubs.acs.org.
corresponding triflate (0.50 mmol), base (1.0 mmol), and olefin (2.0 mmol)
were added to the catalyst solution. The solution was stirred at the desired
temperature under argon. After the desired reaction time, the mixture was
diluted with additional diethyl ether and washed with water, dried over
MgSO4, and evaporated. Conversion and enantiomeric excesses were
determined by gas chromatography with a Chiraldex G-TA column
following ref 2e.
OL052176H
Org. Lett., Vol. 7, No. 25, 2005
5599