Palladium-diphosphite catalysts for the asymmetric allylic substitution reactions

Article abstract of DOI:10.1021/jo0480904

(Chemical Equation Presented) We have designed a series of diphosphite ligands to study the effect of the backbone, the size of the chelate ring, and the substituents of the biphenyl moieties and to determine the scope of this type of ligand in the Pd-catalyzed asymmetric substitution reactions of different types of substrates. Good-to-excellent activities and enantioselectivities have been obtained for disubstituted linear substrate 11 (TOF's up to >2000 mol × (mol × h)^-1, ee values up to 99%) and cyclic substrate 14 (TOF up to 285 mol × (mol × h) ^-1, ee values up to 92%). However, these ligands are inadequate for the Pd-catalyzed allylic alkylation of monosubstituted linear substrates because they provide low enantioselectivities.

Full text of DOI:10.1021/jo0480904

Palladium-Diphosphite Catalysts for the Asymmetric Allylic
Substitution Reactions
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, Campus Sescelades,
C/Marcel‚l ı´ Domingo, s/n. 43007 Tarragona, Spain
montserrat.dieguez@urv.net; oscar.pamies@urv.net
Received October 28, 2004
We have designed a series of diphosphite ligands to study the effect of the backbone, the size of the
chelate ring, and the substituents of the biphenyl moieties and to determine the scope of this type
of ligand in the Pd-catalyzed asymmetric substitution reactions of different types of substrates.
Good-to-excellent activities and enantioselectivities have been obtained for disubstituted linear
-
1
substrate 11 (TOF’s up to >2000 mol × (mol × h) , ee values up to 99%) and cyclic substrate 14
-
1
(
TOF up to 285 mol × (mol × h) , ee values up to 92%). However, these ligands are inadequate for
the Pd-catalyzed allylic alkylation of monosubstituted linear substrates because they provide low
enantioselectivities.
Introduction
However, only one series of diphosphite ligands possess-
ing a furanoside backbone has been used. More research
into the scope of the diphosphite ligands in this process
is therefore needed.
2
One of the main aims of modern synthetic organic
chemistry is the catalytic enantioselective formation of
C-C and C-heteroatom bonds. In this context, pal-
ladium-catalyzed asymmetric allylic substitution is a
powerful and highly versatile procedure. A large number
of chiral ligands, mainly P- and N-containing ligands,
Phosphite ligands are extremely attractive for catalysis
because they are easy to prepare from readily available
alcohols. The variety of alcohols available make simple
ligand tuning possible, enabling the synthesis of many
series of chiral ligands that can be screened in the search
1
2 1
which possess either C - or C -symmetry, have provided
high enantiomeric excesses. Among the P-ligands, diphos-
phines have played a dominant role in the success of
3
for high activity and selectivity. Taking advantage of this
allylic substitution.1d Recently, a group of less electron-
high modularity, in this paper we describe the use of a
series of diphosphite ligands (Figure 1) for studying the
effect of the backbone, the size of the chelate ring, and
the substituents of the biphenyl moieties in the Pd-
catalyzed asymmetric substitution reactions of several
model substrates.
rich phosphorus compoundssdiphosphite ligandsshave
also demonstrated their potential utility in this process,
providing excellent enantioselectivities and activities.2
(
1) For recent reviews, see: (a) Tsuji, J. Palladium Reagents and
Catalysis. In Innovations in Organic Synthesis; Wiley: New York, 1995.
(
b) Trost, B. M.; van Vranken, D. L. Chem. Rev. 1996, 96, 395. (c)
Johannsen, M.; Jorgensen, K. A. Chem. Rev. 1998, 98, 1689. (d) Pfaltz,
A.; Lautens, M. In Comprehensive Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, Germany,
(2) (a) Di e´ guez, M.; Jansat, S.; Gomez, M.; Ruiz, A.; Muller, G.;
Claver, C. Chem. Commun. 2001, 1132. (b) P a` mies, O.; van Strijdonck,
G. P. F.; Di e´ guez, M.; Deerenberg, S.; Net, G.; Ruiz, A.; Claver, C.;
Kamer P. C. J.; van Leeuwen, P. W. N. M. J. Org. Chem. 2001, 66,
8867.
1
2
999; Vol. 2, Chapter 24. (e) Trost, B. M.; Crawley, M. L. Chem. Rev.
003, 103, 2921.
1
0.1021/jo0480904 CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/24/2005
J. Org. Chem. 2005, 70, 3363-3368
3363

Di e´ guez et al.
FIGURE 1. Diphosphite ligands 1-10a-c.
SCHEME 1. Synthesis of the New Diphosphite
Ligands 2, 4, 6-8, 10a
LT iAg Ba nL dE 11 a. a Pd-Catalyzed Allylic Alkylation of 11, Using
b
% eec
entry
solvent
ratio 1a/Pd
% conv (min)
1
2
3
4
5
6
CH2Cl2
DMF
toluene
THF
CH2Cl2
CH2Cl2
1.1
1.1
1.1
1.1
0.9
2
100 (30)
100 (30)
29 (30)
80 (R)
75 (R)
76 (R)
72 (R)
80 (R)
80 (R)
45 (30)
100 (30)
100 (30)
a
0
.5 mol % of [Pd(π-C3H5)Cl]2, 30 min; 3 equiv of CH2(COOMe)2
and N,O-bis(trimethylsilyl)acetamide (BSA), a pinch of KOAc,
b
1
Results and Discussions
room temperature. Measured by H NMR. Reaction time in
c
minutes shown in parentheses. Determined by HPLC (Chiralcel
Ligand Synthesis. The new diphosphite ligands 2, 4,
-8, and 10a were synthesized very efficiently in one
OD).
6
step from the corresponding diols (Scheme 1). The reac-
tion of the corresponding diol with 2 equiv of the desired
in situ-formed phosphorochloridite in the presence of
All the new ligands were stable during purification on
neutral silica gel under an atmosphere of argon and
isolated in moderate-to-good yields (45-78%) as white
solids.
4
base afforded the desired ligands.
Asymmetric Allylic Substitution Reactions. We
first investigated the Pd-catalyzed allylic substitution of
rac-1,3-diphenyl-3-acetoxyprop-1-ene (11), which is widely
used as a model substrate, with dimethyl malonate using
the chiral diphosphite ligands 1-10 (eq 1). The catalysts
(
3) For recent successful application in catalysis, see: (a) Buisman,
G. J. H.; van deer Veen, L. A.; Klootwijk, A.; de Lange, W. G. J.; Kamer,
P. C. J.; van Leeuwen, P. W. N. M.; Vogt, D. Organometallics 1997,
6, 2929. (b) Nozaki, K.; Sakai, N.; Nanno, T.; Higashijima, T.; Mano,
1
S.; Horiuchi, T.; Takaya, H. J. Am. Chem. Soc. 1997, 119, 4413. (c)
Franci o` , G.; Leitner, W. Chem. Commun. 1999, 1663. (d) Di e´ guez, M.;
P a` mies, O.; Ruiz, A.; Castill o´ n, S.; Claver, C. Chem. Commun. 2000,
were generated in situ from 0.5 mol % of π-allyl-
1
607. (e) Di e´ guez, M.; P a` mies, O.; Ruiz, A.; Castill o´ n, S.; Claver, C.
3
palladium chloride dimer [PdCl(η -C
H )]
3 5 2
, the corre-
Chem. Eur. J. 2001, 7, 3086. (f) Pr e´ t oˆ t, R.; Pfaltz, A. Angew. Chem.,
Int. Ed. 1998, 37, 323. (g) Selvakumar, K.; Valentini, M.; Pregosin, P.
S.; Albinati, A. Organometallics 1999, 18, 4591. (h) Dreisbach, C.;
Meseguer, B.; Prinz, T.; Scholz, U.; Militzer, H. C.; Agel, F.; Driessen-
Hoelscher, B. European Patent Appl. 1298136 A2, 2003. (i) Reetz, M.
T.; Neugebauer, T. Angew. Chem., Int. Ed. 1999, 38, 179. (j) Reetz, M.
T.; Goosen, L. J.; Meiswinkel, A.; Paetzol, J.; Jensen, J. F. Org. Lett.
sponding ligand, and a catalytic amount of KOAc.
2
003, 5, 3099. (k) Huang, H.; Zheng, Z.; Luo, H.; Bai, C.; Hu, X.; Chen,
H. Org. Lett. 2003, 5, 4137. (l) Alexakis, A.; Burton, J.; Vastra, J.;
Benhaim, C.; Fournioux, X.; van den Heuvel, A.; Lev eˆ que, J. M.; Maz e´ ,
F.; Rosset, S. Eur. J. Org. Chem. 2000, 4011. (m) Alexakis, A.; Vastra,
J.; Burton, J.; Benhaim, C.; Mangeney, P. Tetrahedron Lett. 1998, 39,
The effects of solvent and ligand-to-palladium ratio
were investigated by using the catalyst precursor con-
taining ligand 1a (Table 1). Our results indicate that (i)
dichloromethane as solvent provides the best combination
of activity and enantioselectivity (entries 1-4) and (ii)
no excess of ligand is necessary for good enantioselec-
7
869. (n) Yan, M.; Yang, L. W.; Wong, K. Y.; Chan, A. S. C. Chem.
Commun. 1999, 11. (o) Yan, M.; Zhou, Z. Y.; Chan, A. S. C. Chem.
Commun. 2000, 115.
(
4) Buisman, G. J. H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.
Tetrahedron: Asymmetry 1993, 4, 1625.
3364 J. Org. Chem., Vol. 70, No. 9, 2005

Catalysts for Asymmetric Allylic Substitution Reactions
TABLE 2. Pd-Catalyzed Allylic Alkylation of 11 with
TABLE 3. Pd-Catalyzed Allylic Amination of 11 with
a
Ligands 1-10a
Ligands 1-10
entry
ligand
% conv (min)b
% eec
1
2
3
4
5
6
7
8
9
1a
2a
3a
4a
5a
6a
7a
8a
9a
10a
3b
3c
3a
3a
100 (30)
82 (30)
100 (5)
93 (5)
100 (30)
100 (30)
84 (30)
30 (30)
60 (30)
87 (30)
100 (5)
43 (30)
100 (30)
100 (30)
80 (R)
18 (S)
94 (R)
73 (R)
10 (S)
3 (S)
% conv (h)b
% eec
entry
ligand
1
2
3
4
5
6
7
8
9
1a
2a
3a
4a
5a
6a
7a
8a
9a
10a
3b
3c
100 (20)
100 (20)
100 (15)
100 (15)
100 (20)
100 (20)
16 (20)
82 (S)
25 (R)
96 (S)
80 (S)
6 (R)
9 (S)
41 (R)
49 (S)
30 (S)
89 (R)
12 (R)
99 (R)
93 (R)
10
11
12
13
14
4 (R)
13 (R)
80 (S)
36 (S)
12 (S)
93 (S)
21 (S)
d
e
19 (20)
32 (20)
1
1
1
0
1
2
42 (20)
a
0
.5 mol % of [Pd(π-C3H5)Cl]2, 1.1 mol % of ligand, room
100 (15)
46 (20)
b
temperature. Conversion percentage of acetate 12 determined
1
by H NMR. Reaction time in minutes shown in parentheses.
c
a
Enantiomeric excesses determined by HPLC on a Chiralcel-OD
0.5 mol % of [Pd(π-C3H5)Cl]2, 1.1 mol % of ligand, room
temperature. Conversion percentage of 13 determined by H
NMR. Reaction time in hours shown in parentheses. Enantio-
meric excesses determined by HPLC on a Chiralcel-OJ column.
Absolute configuration drawn in parentheses.
d
b
1
column. Absolute configuration drawn in parentheses. Reaction
e
c
carried out at 0 °C. Substrate/Pd ratio of 1000.
tivities (entries 1, 5, and 6). Good activity (TOF > 200
-1
mol × (mol × h) ) and enantioselectivity (80% (R) ee)
were therefore both obtained in the alkylation of 11 by
using ligand 1a when dichloromethane was used as
solvent.
Our results indicate that both activities and enantio-
selectivities are higher when bulky tert-butyl substituents
at both ortho and para positions of the biphenyl phosphite
5
moieties are present (entries 3 and 11 vs 12).
For comparative purposes, the rest of the ligands were
tested under the conditions that provided the optimum
tradeoff between enantioselectivities and reaction rates,
i.e., a ligand-to-palladium ratio of 1.1 and dichloro-
methane as solvent. The results, shown in Table 2, indi-
cate that catalytic performance (activities and enantio-
selectivities) is highly affected by the size of the chelate
ring, the backbone, and the substituents of the biphenyl
moieties.
Ligand 2a, which differs from ligand 1a in the intro-
duction of a more rigid pyrrolidine backbone, showed not
only lower activity but also much lower asymmetric
induction (entry 2).
Ligand 3a, which has a longer backbone than ligand
1
a, provided higher activity (TOF > 1200 mol × (mol ×
-1
h) ) and enantioselectivity (94% (R)). Ligand 4a indi-
cated that the presence of the two stereocenters in the
backbone is necessary for high enantioselectivity (entry
3
vs 4).
Ligands 5-10a, which form a nine-membered chelate
ring with the metal center, were less active and enantio-
selective than ligands 3a and 4a, which form an eight-
membered chelate ring (entries 5-10 vs 3 and 4). Ligand
5a, which resembles ligand 3a but has a longer backbone,
therefore showed very low enantioselectivity (entry 5).
Moreover, the results with ligands 5-10 showed that
there is a backbone effect in the enantioselectivity. In
general, ligands containing a more rigid backbone pro-
duced better ee values (entries 8-10 vs 5 and 6). This
behavior contrasts with that of ligands 1 and 2, which
form a seven-membered chelate ring. A plausible expla-
nation for this is that the larger the chelate ring, the
more rigid the backbone needed to control its fluxion-
ability.
Enantioselectivity in cyclic substrates is usually more
difficult to control, mainly because of the presence of less
sterically demanding syn substituents, which are thought
to play a crucial role in the enantioselection observed
with acyclic substrates in the corresponding Pd-allyl
1d
intermediate. Although high enantioselective catalysts
have been developed for cyclic substrates, these systems
generally provide low enantiocontrol in linear sub-
1,6
strates. The development of enantioselective catalysts
for both cyclic and linear substrates is still therefore a
The effect of the different substituents in the ortho and
para positions at the biphenyl phosphite moieties was
studied with ligand backbone 3 (entries 3, 11, and 12).
(
5) These results contrast with those previously published using
furanoside diphosphite ligands, ref 2.
J. Org. Chem, Vol. 70, No. 9, 2005 3365

Di e´ guez et al.
TABLE 4. Pd-Catalyzed Allylic Alkylation of 14, Using
TABLE 6. Selected Results for the Pd-Catalyzed Allylic
Alkylation of 16a
a
Ligand 1a
b
% eec
entry
solvent
ratio 1a/Pd
% conv (h)
1
2
3
4
5
6
CH2Cl2
DMF
Toluene
THF
CH2Cl2
CH2Cl2
1.1
1.1
1.1
1.1
0.9
2
100 (0.5)
100 (0.4)
34 (1)
53 (0.5)
100 (0.5)
100 (0.5)
39 (R)
33 (R)
37 (R)
38 (R)
39 (R)
39 (R)
entry
ligand
% convb
17/18c
% eed
1
2
3
4
1a
3a
5a
8a
75
100
93
16/84
12/88
24/76
13/87
<5
7 (R)
<5
a
0
.5 mol % of [Pd(π-C3H5)Cl]2, 30 min; 3 equiv of CH2(COOMe)2
42
< 5
and N,O-bis(trimethylsilyl)acetamide (BSA), a pinch of KOAc,
b
a
room temperature. Conversion percentage of acetate 15 deter-
All reactions were run at room temperature. Ratio 16/Pd )
mined by GC. Reaction time in hours shown in parentheses.
50. b Conversion percentage by 1H NMR determined after 30 min.
Branched-to-linear ratio determined by GC. Enantiomeric ex-
c
c
d
Enantiomeric excesses determined by GC (FS-â-Cyclodex). Ab-
solute configuration drawn in parentheses.
cesses determined by HPLC on a Chiralcel-OJ column. Absolute
configuration drawn in parentheses.
TABLE 5. Pd-Catalyzed Allylic Alkylation of 14 with
a
Ligands 1-10
1
1. However, enantiomeric excesses and activities were
entry
ligand
% conv (h)b
% eec
lower. Again, the catalyst’s precursor containing the
diphosphite ligand 3a, which forms an eight-membered
chelate ring and has tert-butyl substituents at both ortho
and para positions of the biphenyl phosphite moieties,
provided the best activities (TOF up to 285 mol × (mol
1
2
3
4
5
6
7
8
9
1a
2a
3a
4a
5a
6a
7a
8a
9a
10a
3b
3c
3a
100 (0.5)
100 (0.5)
100 (0.35)
100 (0.35)
100 (0.5)
100 (0.5)
19 (0.5)
39 (R)
33 (S)
74 (S)
45 (S)
4 (R)
-
1
×
h) , entry 3) and enantioselectivities (ee values up to
3 (R)
19 (S)
34 (R)
32 (S)
18 (S)
59 (S)
4 (S)
92%, entry 12).
16 (0.5)
To sum up, our results (Tables 2, 3, and 5) show that
diphosphite ligand 3a offers excellent enantioselectivities
for the Pd-catalyzed asymmetric allylic substitution of
both cyclic and acyclic substrates. It is therefore an
exceptional ligand as it competes favorably with the few
ligands that provide high ee values for both types of
substrates.6
Encouraged by the excellent results obtained so far for
both disubstituted linear and cyclic substrates, we next
applied ligands 1-10 in the Pd-catalyzed allylic alkyl-
ation with dimethyl malonate of a more demanding
substrate: the cinnamyl acetate 16. For this substrate,
the development of highly regio- and enantioselective Pd-
catalysts still represents a challenge. Most Pd catalysts
developed to date favor the formation of the achiral linear
65 (0.5)
10
11
12
12
46 (0.5)
100 (0.35)
23 (0.5)
d
8 (20)
92 (S)
a
0
.5 mol % of [Pd(π-C3H5)Cl]2, 1.1 mol % of ligand, room
b
temperature. Conversion percentage of acetate 15 determined
c
by GC. Reaction time in hours shown in parentheses. Enantio-
meric excesses determined by GC (FS-â-Cyclodex). Absolute con-
figuration drawn in parentheses. d Reaction carried out at -20 °C.
challenge, so we decided to test the chiral ligands 1-10
in the Pd-catalyzed allylic alkylation of 3-acetoxycyclo-
hexene 14 (eq 2), which is usually used as a model cyclic
substrate.
7
product 18 rather than the desired branched isomer 17.
The results are summarized in Table 6. Unfortunately,
the regioselectivity in the desired product 17 and enantio-
selectivity were low. The low enantioselectivity can be
attributed to the fact that these ligands lead to a fast
nucleophilic attack so that there is no time for the
formation of the terminal σ-complex and rotation of the
terminal C-C bond that is known to be necessary to
The preliminary investigations were performed on the
solvent effect, and the ligand-to-palladium ratio with
ligand 1a provided the same trends as those observed in
the previously tested disubstituted linear substrate 11
1
b
obtain high ee values for this kind of substrate.
Conclusion
(
Table 4). The optimum tradeoff between enantioselec-
We have designed a series of diphosphite ligands for
studying the effect of the backbone, the size of the chelate
ring, and the substituents of the biphenyl moieties and
determining the scope of this type of ligands in the Pd-
catalyzed asymmetric substitution reactions of different
types of substrates. Good-to-excellent activities and
enantioselectivities have been obtained for disubstituted
linear substrate 11 (TOF’s up to >2000 mol × (mol ×
tivities and reaction rates was therefore obtained when
dichloromethane was used as solvent and the ligand-to-
palladium ratio was 1.1.
The results of using ligands 1-10 under the optimized
conditions are shown in Table 5. In general, these results
followed the same trend as for the allylic alkylation of
(6) So far only the ligands developed in the groups of Osborn and
-1
h) , ee values up to 99%) and cyclic substrate 14 (TOF
Evans have provided good ee values for both linear and cyclic
substrates. (a) Dierkes, P.; Randechul, S.; Barloy, L.; De Cian, A.;
Fischer, J.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Osborn, J. A.
Angew. Chem., Int. Ed. 1998, 37, 3116. (b) Evans, D. A.; Campos, J.
R.; Tedrow, J. R.; Michael, F. E.; Gagn e´ , M. R. J. Am. Chem. Soc. 2000,
(7) For successful applications of Pd catalysts, see: (a) Pr e´ t oˆ t, R.;
Pfaltz, A. Angew. Chem., Int. Ed. 1998, 37, 323. (b) Hilgraf, R.; Pfaltz,
A. Synlett 1999, 1814. (c) You, S.-L.; Zhu, X.-Z.; Luo, Y.-M.; Hou, X.-
L.; Dai, L.-X. J. Am. Chem. Soc. 2001, 123, 7471.
1
22, 7905.
3366 J. Org. Chem., Vol. 70, No. 9, 2005

Catalysts for Asymmetric Allylic Substitution Reactions
-
1
up to 285 mol × (mol × h) , ee values up to 92%).
However, these ligands are inadequate in terms of
enantioselectivity in the Pd-catalyzed allylic alkylation
of monosubstituted linear substrate 16.
idite (2.2 mmol) produced in situ and (S)-1,3-butanediol (85
µL, 1 mmol), as described for compound 2a, afforded diphos-
phite 4a, which was purified by flash chromatography (toluene/
hexane ) 1/3) to produce a white powder. Yield: 0.45 g, 47%.
2
0
31
1
[
D 3
R] -8.1 (1, CHCl ). P NMR: δ 136.7 (s), 146.4 (s). H
Results obtained in the Pd-catalyzed allylic substitu-
tion reaction of 11 and 14 indicated that enantiomeric
excess is highly affected by the size of the chelate ring
and the substituents of the biphenyl phosphite moieties.
With regard to the size of the chelate ring, enantioselec-
tivities were higher for ligands 3 and 4, which forms an
eight-membered chelate ring, than for ligands that form
a seven-membered chelate ring (ligands 1 and 2) or nine-
membered chelate ring (ligands 5-10). With regard to
the substituents of the biphenyl phosphite moieties, the
highest activities and enantioselectivities were obtained
with ligands containing bulky tert-butyl substituents at
both ortho and para positions of the biphenyl moieties
3
t
NMR: δ 1.21 (d, 3H, JH-H ) 7.2 Hz), 1.37 (s, 9H, CH
3
, Bu),
t
t
1.38 (s, 9H, CH
3
, Bu), 1.39 (s, 9H, CH
3
, Bu), 1.40 (s, 9H, CH ,
3
t
t
t
Bu), 1.48 (s, 9H, CH , Bu), 1.51 (s, 9H, CH , Bu), 1.52 (s,
3
3
t
t
9H, CH
3
, Bu), 1.53 (s, 9H, CH
3 2
, Bu), 1.82 (m, 1H, CH ), 1.96
(m, 1H, CH
2
), 3.89 (m, 2H, CH -O), 4.60 (m, 1H, CH), 7.2-
2
1
3
7
.5 (m, 8H, CHd). C NMR: δ 22.3 (d, CH
3
, JC-P ) 3.8 Hz),
t
t
t
3
1.2 (CH
3
, Bu), 31.3 (CH
3
, Bu), 31.4 (CH
3
t
, Bu), 31.8 (CH
3
,
t
t
t
t
Bu), 31.9 (CH
3
, Bu), 34.7 (C, Bu), 34.8 (C, Bu), 35.5 (C, Bu),
t
3
5.6 (C, Bu), 39.3 (m, CH
14.5 Hz), 122.6 (CHd), 124.3 (CHd), 124.4 (CHd), 125.1
CHd), 125.5 (CHd), 126.8 (CHd), 128.5 (CHd), 129.3 (CHd),
32.9 (C), 133.2 (C), 140.0 (C), 140.1 (C), 140.2 (C), 140.3 (C),
146.4 (C), 146.5 (C), 146.6 (C). Anal. Calcd (%) for C H O P :
2 2
), 61.5 (CH -O), 70.2 (d, CH, JC-P
)
(
1
60
88
6
2
C 74.50, H 9.17. Found: C 74.43, H 9.22.
(
a).
4,5-Bis[(3,3′,5,5′-tetra-tert-butyl-1,1′-biphenyl-2,2′-diyl)-
phosphite]-2,2-dimethyl-1,3-dioxolane (6a). Treatment of
phosphorochloridite (2.2 mmol) produced in situ and (-)-2,3-
O-isopropylidene-D-threitol (162.2 mg, 1 mmol), as described
for compound 2a, afforded diphosphite 6a, which was purified
by flash chromatography (toluene/hexane ) 1/3) to produce a
Experimental Section
General Considerations. All reactions were carried out
with standard Schlenk techniques under an atmosphere of
argon. Solvents were purified and dried by standard proce-
2
0
31
white powder. Yield: 0.66 g, 65%. [R]
D
+57 (1, CHCl
3
).
P
1
8
8
8
3i
NMR: δ 134.5 (s). H NMR: δ 1.29 (s, 6H, CH ), 1.35 (s, 36H,
3
dures. Diphosphite ligands 1a, 3a-c, 5a, and 9a and
t
t
t
4
CH
3 3
, Bu), 1.45 (s, 18H, CH3, Bu), 1.47 (s, 18H, CH , Bu), 3.78
phosphorochloridite were prepared as previously described.
1
3
9
(m, 4H, CH
NMR: δ 27.3 (CH
2
), 3.86 (m, 2H, CH), 7.1-7.5 (m, 8H, CHd).
C
3
Racemic 1,3-diphenyl-3-acetoxyprop-1-ene (11) and 3-acetoxy-
t
t
1
0
1
3
), 31.1 (CH
3
, Bu), 31.2 (CH
3
t
, Bu), 31.3 (CH
,
cyclohexene (14) were prepared as previously reported. H,
t
t
t
1
3
1
31
1
Bu), 31.8 (CH , Bu), 34.9 (C, Bu), 35.6 (C, Bu), 64.3 (CH ),
C{ H}, and P{ H} NMR spectra were recorded on a 400
MHz spectrometer. Chemical shifts are relative to that of
3
2
7
7.2 (CH), 110.2 (C), 124.4 (CHd), 125.5 (CHd), 126.7 (CHd),
1
13
31
126.8 (CHd), 128.5 (CHd), 129.3 (CHd), 132.6 (C), 132.7 (C),
SiMe
4 3 4
( H and C) as internal standard or H PO ( P) as
1
32.8 (C), 132.9 (C), 139.9 (C), 140.2 (C), 146.2 (C), 146.3 (C),
external standard. All assignments in NMR spectra were
1
1
13
1
146.6 (C), 146.7 (C). Anal. Calcd (%) for C H O P : C 72.80,
determined by H- H (COSY) and C- H (HSQC) spectra.
-Benzyl-3,4-bis[(3,3′,5,5′-tetra-tert-butyl-1,1′-biphenyl-
,2′-diyl)phosphite]pyrrolidine (2a). Phosphorochloridite
2.2 mmol) produced in situ was dissolved in toluene (5 mL),
63 92
8
2
H 8.92. Found: C 72.65, H 8.91.
1
2
(
(R)-2,2′-Bis[(3,3′,5,5′-tetra-tert-butyl-1,1′-biphenyl-2,2′-
diyl)phosphite]-1,1′-binaphthyl (7a). Treatment of phos-
phorochloridite (2.2 mmol) produced in situ and (R)-binaphthol
(286.3 mg, 1 mmol), as described for compound 2a, afforded
diphosphite 7a, which was purified by flash chromatography
(toluene/hexane ) 1/3) to produce a white powder. Yield: 0.51
and pyridine (0.36 mL, 4.6 mmol) was added. 1-Benzyl-3,4-
pyrrolidinediol (193.2 mg, 1 mmol) was azeotropically dried
with toluene (3 × 1 mL) and then dissolved in toluene (10 mL),
to which pyridine (0.18 mL, 2.3 mmol) was added. The diol
solution was transferred slowly over 30 min at room temper-
ature to the solution of phosphorochloridite. The reaction
mixture was stirred overnight at 80 °C, and the pyridine salts
were removed by filtration. Evaporation of the solvent gave a
white foam, which was purified by flash chromatography
2
0
31
3
1
g, 45%. [R]
D
-11.6 (1, CHCl ). P NMR: δ 131.8 (s). H
t
t
NMR: δ 1.09 (s, 9H, CH , Bu), 1.12 (s, 9H, CH , Bu), 1.33 (s,
3
3
t
t
t
18H, CH , Bu), 1.34 (s, 9H, CH , Bu), 1.36 (s, 9H, CH , Bu),
3
3
3
t
13
1.46 (s, 18H, CH , Bu), 7.1-8.0 (m, 20H, CHd). C NMR: δ
3
t
t
t
t
30.9 (CH ,
3
Bu), 31.0 (CH ,
3
Bu), 31.3 (CH ,
Bu), 35.3 (C,
3
Bu), 35.0 (C,
Bu),
Bu), 121.8 (CHd), 122.1
CHd), 122.2 (CHd), 123.3 (CHd), 123.6 (CHd), 124.8 (CHd),
(
toluene/hexane ) 1/1) to produce a white powder. Yield: 0.48
35.1 (C,
t
Bu), 35.2 (C,
t
t
2
0
31
1
g, 45%. [R]
D 3
-54 (0.25, CHCl ). P NMR: δ 143.3 (s). H
t
(
t
3
NMR: δ 1.37 (s, 18H, CH , Bu), 1.39 (s, 18H, CH3, Bu), 1.44
1
25.1 (CHd), 125.9 (CHd), 126.5 (CHd), 126.7 (CHd), 128.3
CHd), 128.5 (CHd), 128.9 (CHd), 129.1 (CHd), 130.2 (C),
t
t
(
3 3 2
s, 18H, CH , Bu), 1.48 (s, 18H, CH , Bu), 2.43 (dd, 2H, CH ,
J
(
3
2
3
H-H ) 3.6 Hz, JH-H ) 11.2 Hz), 2.72 (dd, 2H, CH
.0 Hz, JH-H ) 11.2 Hz), 3.32 (d, 1H, CH
2
, JH-H
)
1
1
1
31.7 (C), 132.2 (C), 133.2 (C), 137.1 (C), 137.6 (C), 137.7 (C),
39.4 (C), 139.8 (C), 145.3(C), 145.5 (C), 146.4 (C), 146.8 (C),
2
2
6
2
-N, JH-H ) 12.8
2
Hz), 3.48 (d, 1H, CH
2
-N, JH-H ) 12.8 Hz), 4.82 (m, 2H, CH),
46.9 (C), 147.8 (C). Anal. Calcd (%) for C76
92 6 2
H O P : C 78.45,
1
3
t
7
.2-7.5 (m, 13H, CHd). C NMR: δ 31.4 (CH
3
, Bu), 31.5
H 7.97. Found: C 78.31, H 8.02.
S)-2,2′-Bis[(3,3′,5,5′-tetra-tert-butyl-1,1′-biphenyl-2,2′-
t
t
t
t
(
(
CH
3
, Bu), 31.6 (CH
3
, Bu), 31.8 (CH
3
, Bu), 34.8 (C, Bu), 34.8
(
t
t
t
t
C, Bu), 34.9 (C, Bu), 35.5 (C, Bu), 35.6 (C, Bu), 59.4 (CH
2
),
diyl)phosphite]-1,1′-binaphthyl (8a). Treatment of phos-
phorochloridite (2.2 mmol) produced in situ and (S)-binaphthol
6
0.2 (CH
d, CHd, JC-P ) 5.3 Hz), 127.3 (CHd), 128.5 (d, CHd, JC-P
.4 Hz), 129.1 (CHd), 129.3 (CHd), 132.8 (C), 133.1 (C), 138.1
C), 138.2 (C), 140.2 (C), 140.3 (C), 145.8 (C), 146.2 (C), 146.5
C), 146.7 (C). Anal. Calcd (%) for C67 : C 75.18, H
.76, N 1.31. Found: C 75.23, H 8.71, N 1.39.
S)-1,3-Bis[(3,3′,5,5′-tetra-tert-butyl-1,1′-biphenyl-2,2′-
diyl)phosphite]butane (4a). Treatment of phosphorochlor-
2
-N), 80.5 (m, CH), 124.4 (CHd), 125.5 (CHd), 126.7
(
)
(
286.3 mg, 1 mmol), as described for compound 2a, afforded
4
diphosphite 8a, which was purified by flash chromatography
(
(
(
toluene/hexane ) 1/3) to produce a white powder. Yield: 0.57
H
6 2
93NO P
2
0
31
1
g, 49%. [R]
D
+11.6 (1, CHCl
3
). P NMR: δ 131.8 (s).
H
8
t
t
NMR: δ 1.12 (s, 18H, CH
3
, Bu), 1.16 (s, 18H, CH
3
, Bu), 1.38
(
t
t
(
3 3
s, 18H, CH , Bu), 1.40 (s, 18H, CH , Bu), 7.1-8.0 (m, 20H,
13
t
t
CHd). C NMR: δ 30.9 (CH
3
t
, Bu), 31.0 (CH
3
, Bu), 31.7 (CH
3
,
t
t
t
Bu), 34.8 (C, Bu), 34.9 (C, Bu), 35.3 (C, Bu), 122.7 (CHd),
(8) Buisman, G. J. H.; Vos, E. J.; Kamer, P. C. J.; van Leeuwen, P.
123.0 (CHd), 123.3 (CHd), 124.4 (CHd), 124.5 (CHd), 124.9
CHd), 125.5 (CHd), 126.6 (CHd), 126.7 (CHd), 126.8 (CHd),
28.1 (CHd), 128.4 (CHd), 129.0 (CHd), 129.3 (CHd), 130.9
W. N. M. J. Chem. Soc., Dalton Trans. 1995, 409.
(
(
9) Auburn, P. R.; Mackenzie, P. B.; Bosnich B. J. Am. Chem. Soc.
985, 107, 2033.
10) Jia, C.; M u¨ ller, P.; Mimoun, H. J. Mol. Catal. A: Chem. 1995,
01, 127.
1
1
(
C), 132.6 (C), 133.2 (C), 134.2 (C), 138.1 (C), 138.6 (C), 138.7
(
1
(C), 140.4 (C), 140.8 (C), 145.4 (C), 145.5 (C), 146.4 (C), 146.8
J. Org. Chem, Vol. 70, No. 9, 2005 3367

Di e´ guez et al.
(
C), 146.9 (C), 147.9 (C). Anal. Calcd (%) for C76
8.45, H 7.97. Found: C 78.52, H 8.07.
,5-Bis[(3,3′,5,5′-tetra-tert-butyl-1,1′-biphenyl-2,2′-diyl)-
H
92
O
6
P
2
: C
After 30 min the reaction mixture was diluted with Et
mL) and saturated NH Cl (aq) (25 mL) was added. The
mixture was extracted with Et
O (3 × 10 mL) and the extract
dried over MgSO . Conversion and enantiomeric excess was
determined by GC, using a FS-â-Cyclodex 25 m column F.I.D.
detector (internal diameter 0.2 mm; film thickness 0.33 mm;
carrier gas 100 kPa He).
2
O (5
7
4
2
2
phosphite]-1,4:3,6-dianhydro-D-sorbide (10a). Treatment
of phosphorochloridite (2.2 mmol) produced in situ and iso-
sorbide (146 mg, 1 mmol), as described for compound 2a,
afforded diphosphite 10a, which was purified by flash chro-
matography (toluene/hexane ) 1/1) to produce a white powder.
4
Allylic Alkylation of Cinnamyl Acetate (16). A degassed
2
0
31
Yield: 0.79 g, 78%.[R]
D
+19.9 (1, CHCl
3
). P NMR: δ 136.2
3
3 5 2
solution of [PdCl(η -C H )] (1.8 mg, 0.005 mmol) and the
1
t
(
s), 140.1 (s). H NMR: δ 1.34 (s, 9H, CH
3
, Bu), 1.35 (s, 27H,
diphosphite ligand (0.011 mmol) in dichloromethane (0.5 mL)
was stirred for 30 min. Subsequently, a solution of rac-16 (88.1
mg, 0.5 mmol) in dichloromethane (1.5 mL), dimethyl malonate
t
t
t
CH
3
, Bu), 1.44 (s, 9H, CH
3
, Bu), 1.45 (s, 9H, CH
3
, Bu), 1.46
, Bu), 3.37 (m, 1H, CH ),
t
t
(
s, 9H, CH
3
, Bu), 1.49 (s, 9H, CH
3
2
3
2
3
.63 (m, 1H, CH
2
), 3.80 (dd, 1H, CH
2
, JH-H ) 4.0 Hz, JH-H
, JH-H ) 10.8 Hz), 4.28 (m, 1H,
)
(
171 µL, 1.5 mmol), N,O-bis(trimethylsilyl)acetamide (370 µL,
.5 mmol), and a pinch of KOAc were added. The reaction
mixture was stirred at room temperature. After 5 min the
reaction mixture was diluted with Et O (5 mL) and saturated
NH Cl (aq) (25 mL) was added. The mixture was extracted
with Et
2
1
0.8 Hz), 3.91 (bd, 1H, CH
2
1
CH), 4.35 (m, 2H, CH), 4.51 (m, 1H, CH), 7.1-7.5 (m, 8H,
13
t
t
CHd). C NMR: δ 31.2 (CH
3
, Bu), 31.3 (CH
3
, Bu), 31.4 (CH
3
,
2
t
t
t
t
t
Bu), 31.7 (CH
0.0 (CH ), 74.9 (CH
CH), 124.4 (CHd), 124.6 (CHd), 124.6 (CHd), 126.8 (CHd),
28.5 (CHd), 129.3 (CHd), 131.8 (C), 131.9 (C), 132.5 (C), 132.8
C), 140.0 (C), 140.1 (C), 140.3 (C), 140.4 (C), 146.7 (C), 146.8
C), 146.9 (C), 147.0 (C). Anal. Calcd (%) for C64 : C
3
, Bu), 34.9 (C, Bu), 35.5 (C, Bu), 35.6 (C, Bu),
4
7
2
2
), 75,4 (CH), 79.7 (CH), 80.9 (CH), 86.8
2
O (3 × 10 mL) and the extract dried over MgSO
4
.
(
Solvent was removed and conversion and regioselectivity
1
1
were measured by H NMR. To determine the ee by HPLC
(
(
(
Chiralcel-OJ, 3% 2-propanol/hexane, flow 0.7 mL/min), a
92 6 2
H O P
sample was filtered over basic alumina with dichloromethane
as the eluent.
7
5.41, H 9.10. Found: C 75.54, H 9.06.
Allylic Alkylation of rac-1,3-diphenyl-3-acetoxyprop-
Allylic Amination of rac-1,3-Diphenyl-3-acetoxyprop-
3
1
0
-ene (11). A degassed solution of [PdCl(η -C
3 5 2
H )] (0.9 mg,
3
1
0
-ene (11). A degassed solution of [PdCl(η -C
3
H
5
)]
2
(0.9 mg,
.0025 mmol) and the diphosphite ligand (0.0055 mmol) in
.0025 mmol) and the diphosphite ligand (0.0055 mmol) in
dichloromethane (0.5 mL) was stirred for 30 min. Subse-
quently, a solution of rac-11 (126 mg, 0.5 mmol) in dichloro-
methane (1.5 mL), dimethyl malonate (171 µL, 1.5 mmol), N,O-
bis(trimethylsilyl)acetamide (370 µL, 1.5 mmol), and a pinch
of KOAc were added. The reaction mixture was stirred at room
temperature. After 5 min the reaction mixture was diluted
with Et
added. The mixture was extracted with Et
the extract dried over MgSO . Solvent was removed and
conversion was measured by H NMR. To determine the ee
by HPLC (Chiralcel-OD, 0.5% 2-propanol/hexane, flow 0.5 mL/
min), a sample was filtered over basic alumina, using di-
chloromethane as the eluent.
dichloromethane (0.5 mL) was stirred for 30 min. Subse-
quently, a solution of rac-11 (126 mg, 0.5 mmol) and benzyl-
amine (131 µL, 1.5 mmol) in dichloromethane (1.5 mL) was
added. The reaction mixture was stirred at room temperature.
After 1 h the reaction mixture was diluted with Et
and saturated NH Cl (aq) (25 mL) was added. The mixture
was extracted with Et
O (3 × 10 mL) and the extract dried
over MgSO . Solvent was removed and conversion was mea-
2
O (5 mL)
4
2
O (5 mL) and saturated NH
4
Cl (aq) (25 mL) was
2
2
O (3 × 10 mL) and
4
4
1
sured by H NMR. To determine the ee by HPLC (Chiralcel-
OJ, 13% 2-propanol/hexane, flow 0.5 mL/min), a sample was
1
filtered over silica with 10% Et
2
O/hexane mixture as the
eluent.
Allylic Alkylation of rac-3-Acetoxycyclohexene (14).
3
A degassed solution of [PdCl(η -C
H )]
3 5 2
(0.9 mg, 0.0025 mmol)
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.)
and the diphosphite ligand (0.0055 mmol) in dichloromethane
0.5 mL) was stirred for 30 min. Subsequently, a solution of
(
rac-14 (70 mg, 0.5 mmol) in dichloromethane (1.5 mL),
dimethyl malonate (171 µL, 1.5 mmol), N,O-bis(trimethylsilyl)-
acetamide (370 µL, 1.5 mmol), and a pinch of KOAc were
added. The reaction mixture was stirred at room temperature.
JO0480904
3368 J. Org. Chem., Vol. 70, No. 9, 2005