Facile synthesis of proline based phosphine-oxazoline ligands by formation of a P-N bond

Article abstract of DOI:10.1016/S0040-4039(02)00346-5

A series of new P-N ligands in which the phosphorus moiety is introduced by formation of a phosphorus-heteroatom bond are synthesized. These ligands are based on proline with chiral centers from both proline and an oxazoline. The two chiral centers are re

Full text of DOI:10.1016/S0040-4039(02)00346-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2811–2814
Facile synthesis of proline based phosphineꢀoxazoline ligands by
formation of a PꢀN bond
Guopin Xu and Scott R. Gilbertson*
Department of Chemistry, Washington University, St. Louis, MO 63130, USA
Received 14 January 2002; revised 16 February 2002; accepted 18 February 2002
Abstract—A series of new PꢀN ligands in which the phosphorus moiety is introduced by formation of a phosphorusꢀheteroatom
bond are synthesized. These ligands are based on proline with chiral centers from both proline and an oxazoline. The two chiral
centers are responsible for the observed stereoselectivity. Palladium complexes of these ligands are shown to be effective in the
allylation of dimethyl malonate as well as amination of allyl acetates. © 2002 Elsevier Science Ltd. All rights reserved.
Phosphine ligands have proven to be one of the most
successful types of ligands in asymmetric catalysis. As a
measure of this, there have been hundreds of chiral
phosphine ligands tested and used in asymmetric cataly-
sis.1–6 One of the fundamental problems with the use
tion of phosphorus.4,9,10 This paper reports the synthe-
sis of a series of ligands (1–5) of this type, four of which
are based on proline. The use of these ligands in
palladium-catalyzed allylations, allyl aminations is
reported.
of phosphine ligands has been the relative difficulty
with their synthesis. The formation of PꢀC bonds gen-
erally requires reaction conditions that are not suitable
to the synthesis of highly funtionalized ligands or the
synthesis of multiple ligands in parallel.7,8 For this
reason a number of people have used the formation of
a P-hetero-atom bond as the method for the incorpora-
The desired ligands are readily available (Scheme 1) by
reacting the benzyl ester of proline with diphenylphos-
phine chloride. Following the formation of the PꢀN
bond, the phosphorus is protected as the phosphine
sulfide (7) by reaction with elemental sulfur. After this
transformation the benzyl ester is removed by treat-
ment with lithium iodide (8). Despite the elevated tem-
Scheme 1.
* Corresponding author. Tel.: 1-314-935-6357; fax: 1-314-935-4481; e-mail: srg@wuchem.wustl.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00346-5

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G. Xu, S. R. Gilbertson / Tetrahedron Letters 43 (2002) 2811–2814
perature there is no racemization of the proline. This is
readily apparent when in the next step the amino ester,
that will ultimately become the oxazoline, is coupled to
the free acid (8). Following amide formation the ester is
reduced to the alcohol and this molecule is cyclized to
the oxazoline (11 and 12). Prior to use the phosphine
sulfide is reduced to the phosphine with Raney nickel.†
The selectivity in a number of solvents was determined
using ligand 1 and diphenyl allyl acetate as the model
substrate (Table 1, entries 1–6). Acetonitrile was found
to be the best solvent, giving the allylation product in
96% yield and 94% ee (Table 1, entry 1). The selectivity
appears to be relatively insensitive to solvent effects
with a number of solvents giving 90% ee or better. The
Table 1. Palladium-catalyzed allylationa
Entry
1
Substrate
Pd source/Temp.
Ligand
1
Solvent
CH3CN
Yield (%)
96
Eeb (%)
[Pd(h3-C3H5)Cl]2/rt
94 (R)
2
3
4
5
6
7
8
9
[Pd(h3-C3H5)Cl]2/rt
[Pd(h3-C3H5)Cl]2/rt
[Pd(h3-C3H5)Cl]2/rt
[Pd(h3-C3H5)Cl]2/rt
[Pd(h3-C3H5)Cl]2/rt
[Pd(h3-C3H5)Cl]2/rt
[Pd(h3-C3H5)Cl]2/rt
[Pd(h3-C3H5)Cl]2/rt
[Pd(h3-C3H5)Cl]2/rt
[Pd(h3-C3H5)Cl]2/rt
1
1
1
1
1
2
3
4
5
1
THF
94
95
94
97
96
98
90
91
97
93
89 (R)
90 (R)
85 (R)
92 (R)
90 (R)
25 (S)
56 (R)
65 (R)
41 (R)
44 (R)
CH2Cl2
Cl(CH2)2Cl
Benzene
Toluene
CH3CN
CH3CN
CH3CN
CH3CN
Benzene
10
11
12
13
14
15
[Pd(h3-C3H5)Cl]2/rt
[Pd(h3-C3H5)Cl]2/rt
[Pd(h3-C3H5)Cl]2/−20°C
[Pd(h3-C3H5)Cl]2/rt
1
1
1
1
Toluene
CH3CN
CH3CN
CH3CN
90
91
87
98
40 (R)
35 (R)
39 (R)
10 (R)
16
17
[Pd(h3-C3H5)Cl]2/rt
[Pd(h3-C3H5)Cl]2/rt
2
5
CH3CN
CH3CN
93
94
10 (S)
5 (R)
a 4.5 mol% ligand, 2 mol% [Pd(allyl)Cl]2, 3 equiv., dimethyl malonate, 3 equiv. BSA, 3 equiv. TBAF, 12 h.
b The selectivities for entries 1–10 were determined by HPLC on Chiralpak AD, hexanes/isopropyl alcohol=9:1, flow rate of 1.0 mL/min. For
entries 11–17 selectivities were determined by chiral shift reagent [Eu(hfc)]3.
† Representive spectral data:
Amide 9
1H NMR (300 MHz, CDCl3) l 7.90–7.83 (m, 4H), 7.49–7.37 (m, 6H), 6.99 (bd, J=7.8 Hz, 1H), 4.18–4.11 (m, 1H), 3.58–3.54 (m, 2H), 3.18–3.11
(m, 2H), 2.18–2.07 (m, 3H), 1.93–1.76 (m, 3H), 0.87 (d, J=9.0 Hz, 3H), 0.85 (d, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) l 174.1, 132.4,
132.2, 132.1, 132.0, 128.9, 128.7, 64.1, 62.4 (d, Jp–c=3.2 Hz), 57.8, 49.3, 31.4 (d, Jp–c=4.3 Hz), 29.4, 25.9 (d, Jp–c=5.4 Hz), 19.6, 19.2; 31P NMR
(125 MHz, CDCl3) l 66.3; HRMS (FAB) calcd for C22H29N2O2PSLi+ 423.1847 found 423.1866.
Amide 10
1H NMR (300 MHz, CDCl3) l 8.03–7.96 (m, 2H), 7.89–7.85 (m, 2H), 7.65 (bd, J=7.2 Hz, 1H), 7.55–7.22 (m, 11 H), 5.39 (d, J=7.2 Hz, 1H),
4.13–4.06 (m, 1H), 3.74 (s, 3H), 3.36–3.22 (m, 2H), 2.22–2.10 (m, 2H), 1.99–1.91 (m, 2H); 13C NMR (75 MHz, CDCl3) l 172.2, 171.5, 136.4,
132.5, 132.4, 132.3, 132.1, 129.2, 129.0, 128.9, 128.9, 128.7, 128.6, 127.5, 62.5, 56.5, 53.1, 48.9, 31.7, 25.5 (d, Jp–c=4.6 Hz); 31P NMR (125 MHz,
CDCl3) l 69.5; HRMS (FAB) calcd for C26H27Li+N2O3PS 485.1640, found 485.1642.
Oxazoline phosphine sulfide 11
1H NMR (300 MHz, CDCl3) l 8.20–8.03 (m, 4H), 7.50–7.27 (m, 6H), 4.30–4.21 (m, 1H), 4.10–4.04 (t, J=8.4 Hz, 1H), 3.85–3.79 (t, J=8.4 Hz,
1H), 3.77–3.69 (m, 1H), 3.36–3.16 (m, 2H), 2.22–2.10 (m, 1H), 2.02–1.88 (m, 2H), 1.65–1.52 (m, 1H), 0.88 (d, J=6.9 Hz, 3H), 0.82 (d, J=6.9
Hz, 3H); 13C NMR (75 MHz, CDCl3) l 168.3, 132.8, 132.7, 132.6, 132.6, 131.8, 131.8, 128.6, 128.5, 128.3, 128.1, 72.4, 70.5, 56.2 (d, Jp–c=4.0
Hz), 48.6 (d, Jp–c=2.0 Hz), 32.8, 31.7, 25.8 (d, Jp–c=4.8 Hz), 19.3, 18.5; 31P NMR (125 MHz, CDCl3) l 68.0; HRMS (FAB) calcd for
C22H27Li+N2OPS 405.1742 found 405.1761.
Oxazoline phosphine sulfide 12
1H NMR (300 MHz, CDCl3) l 8.19–8.06 (m, 4H), 7.44–7.26 (m, 11H), 4.52 (dd, J=9.3, 8.4 Hz, 1H), 4.43 (dd, J=9.3, 8.4 Hz, 1H), 4.01–3.88
(m, 2H), 3.30–3.18 (m, 2H), 2.25–1.95 (m, 2H); 13C NMR (75 MHz, CDCl3) l 170.3, 142.3, 132.8, 132.7, 132.6, 132.6, 132.5, 132.5, 131.9, 129.0,
128.9, 128.7, 128.6, 128.4, 128.9, 128.8; 75.0, 69.7, 56.3, 48.8 (d, Jp–c=6.5 Hz), 33.2, 29.9, 25.8 (d, Jp–c=4.9 Hz); 31P NMR (125 MHz, CDCl3)
l 68.5; HRMS (FAB) calcd for C25H25Li+N2OPS 439.1585 found 439.1579.

G. Xu, S. R. Gilbertson / Tetrahedron Letters 43 (2002) 2811–2814
2813
type of base used to generate the malonate anion was
also examined. The BSA/TBAF system (94% ee) devel-
oped in our laboratory11 appears to be superior to
BSA/KOAc (84% ee) or BSA/NaOAc (63% ee). Lig-
ands 2–5 were also examined. These ligands provided
significantly lower selectivity. Ligand 1, with an isopro-
pyl on the oxazoline, proved to be the best ligand. The
chiral center on the oxazoline of ligand 2 appears to be
no longer complementary to the chirality of the proline.
It is also observed that the phenyl ring on ligand 3 and
the geminal dimethyl groups on ligand 4 do not offer
the same steric hindrance as an isopropyl group on
ligand 1. In other proline based ligands we have found
oxazolines such as ligand 4 to be effective at inducing
asymmetric induction.11–14
Nitrogen based nucleophiles where also examined with
this ligand system.15–23 When 1,3-diphenylprop-2-enyl
acetate was used both benzyl amine and phthalimide
potassium salt were found to be effective nucleophiles.
Benzyl amine added up to 93% ee (Table 2, entry 1)
while phthalimide added with good selectivity (91% ee)
but low yield (29%) (Table 2, entry 4). In the case of
benzyl amine addition, changing the palladium source
to [Pd(allyl)Cl]2 or changing the temperature (Table 2,
entries 2 and 3) resulted in a decrease in selectivity. The
addition to dimethyl 2-acetoxy-3-pentene and cyclopen-
tenyl acetate proceeded with moderate selectivity, 56%
and 48% ee, respectively.
Ligand 5 was synthesized to determine the influence of
the proline chirality. This ligand has the same type and
number of atoms between the oxazoline nitrogen and
the phosphorus as ligands 1–4. However, it lacks the
chiral rigid structure of the proline five member ring as
well as the proline chiral center. As can be seen the
selectivity for both the reaction with malonate and the
nitrogen nucleophiles is generally lower than the ligands
containing proline.
Additionally a number of substrates were examined. As
is often the case, substrates other than diphenyl allyl
acetate resulted in moderate to low selectivities.
Aliphatic acyclic allyl acetates (Table 1, entries 11–14)
proceeded with selectivities up to 44% ee while the
difficult substrate cyclopentenyl acetate gave the desired
product in only 10% ee (Table 1, entries 15–17).
Table 2. Addition of nitrogen nucleophiles
Entry
1
Substrate
Nucleophile
BnNH2
Ligand
1
Solvent
THF
Yield (%)
97
Eeb (%)
93 (S)a
2
3
4
5
6
7
8
9
BnNH2
BnNH2
Phthalimide
BnNH2
Phthalimide
BnNH2
BnNH2
Phthalimide
BnNH2
Phthalimide
BnNH2
1
1
1
2
2
3
4
4
5
5
1
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
95
70
29
97
72
93
97
36
95
33
79
88 (S)c
89 (S)a,d
91 (S)a,e
81 (R)a
89 (R)a,f
14 (S)a
54 (S)a
25 (S)a,e
78 (S)a
90 (S)a,e
56a
10
11
12
13
BnNH2
1
THF
89
48a
14
Phthalimide
5
THF
76
9a,f
a 4.5 mol % ligand, 2 mol % Pd2(dba)2 3 equiv., nucleophile, reaction time 12 h at room temperature.
b ee was determined by HPLC on Daicel Chiralcel OD column, hexanes/isopropyl alcohol=100:1, flow rate of 0.5 mL/min.
c [Pd(allyl)Cl]2 was the palladium source.
d Reaction temperature 0°C.
e Reaction temperature 0°C.
f Reaction temperature reflux.

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G. Xu, S. R. Gilbertson / Tetrahedron Letters 43 (2002) 2811–2814
A proline-based PꢀN ligand system has been developed.
The system has proven to be effective as a catalyst for
the palladium-catalyzed addition to diphenyl allyl ace-
tate. The selectivities obtained with other substrates
were lower, however comparable to a number of others
systems that have been investigated. One of the key
features of this system is the ease with which the desired
ligands were synthesized. Clearly formation of a PꢀN
bond is easier then a PꢀC bond. It is becoming clear
that discreet complexes where the phosphorus is linked
through a heteroatom are viable ligands for asymmetric
catalysis.
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Acknowledgements
This work was partially supported by NIH R01
GM56490, NSFcCHE-97236, Washington University.
We also gratefully acknowledge the Washington Uni-
versity High-Resolution NMR Facility, partially sup-
ported by NIH 1S10R02004, and the Washington
University Mass Spectrometry Resource Center, par-
tially supported by NIHRR00954, for their assistance.
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