Ferrocenylphosphine-amide ligands for palladium-catalyzed asymmetric allylation

Article abstract of DOI:10.1016/j.tetasy.2004.04.043

A new series of phosphine-amide ligands has been prepared on a ferrocenylethyl backbone. These species are effective for enantioselective palladium-catalyzed substitution reactions of allylic acetates. The modular nature of the ligand design has allowed r

Full text of DOI:10.1016/j.tetasy.2004.04.043

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2151–2154
Ferrocenylphosphine-amide ligands for palladium-catalyzed
asymmetric allylation
*
Neil W. Boaz, James A. Ponasik, Jr., Shannon E. Large and Sheryl D. Debenham
Research Laboratories, Eastman Chemical Company, PO Box 1972, Kingsport, TN37662, USA
Received 5 April 2004; accepted 29 April 2004
Available online 11 June 2004
Abstract—A new series of phosphine-amide ligands has been prepared on a ferrocenylethyl backbone. These species are effective for
enantioselective palladium-catalyzed substitution reactions of allylic acetates. The modular nature of the ligand design has allowed
ready optimization to afford products of up to 98.8% ee.
ꢀ
2004 Elsevier Ltd. All rights reserved.
2
The asymmetric alkylation of allylic electrophiles cata-
lyzed by palladium complexes has been extensively
investigated due to the synthetic potential of the prod-
ucts of these types of reactions. A wide variety of ligands
have been found to be effective for these transforma-
late. We were interested in examining the effect of a
potentially larger chelate ring size (eight membered).
Conversion of ferrocenyl phosphine-amines 2 to ferro-
cenyl phosphine-amides 1 occurred in a straightforward
manner by reaction with either an acid chloride or
anhydride. These materials were generally readily iso-
lable crystalline solids that often precipitated from the
1
tions. One particular class of ligands that has received
2
little attention has been the phosphine-amide ligands.
;3
This is likely because the enantioselectivities achieved
using these species are generally below 90% ee. This is
perhaps not surprising, as many of the species prepared
to date have been derived from phosphinobenzoic acid,
with the chirality remote from the reaction center,
residing on the conformationally labile amino portion of
the amide. We reasoned that if the chirality was placed
on the backbone of the molecule the transfer of stereo-
chemical information might be more efficient. Our
interest was augmented by our ready access to chiral
amino-phosphine precursors, ferrocenyl species 2, which
are the final intermediates in the synthesis of a variety of
recently introduced ferrocenyl phosphine-aminophos-
5
acylation reaction mixture. As shown in Scheme 1, a
0
variety of species with variation of both the R and R
groups was prepared.
R
R'COCl or
R'CO) O
R
N
N
(
2
R'
H
Fe PPh2
Fe PPh2
O
Et N
3
PhCH
3
2
1
a: R = H, R' = CH3
b: R = H, R' = Et
c: R = H, R' = t-Bu
d: R = H, R' = Ph
f: R = R' = CH3
4
phine ligands for asymmetric hydrogenation. The
g: R = CH , R' = Et
3
amides 1 derived from phosphine-amines 2 seemed ideal
species to investigate, as these molecules possess two
modes of chirality (planar and side chain) that are both
held in fairly rigid conformations. In addition, the
binding of the previously prepared phosphine-amides to
palladium has been shown to occur through the phos-
phine and amide oxygen to afford a six-membered che-
h: R = Ph, R' = Et
2
i: R = CH Ph, R' = CH3
e: R = H, R' = Ot-Bu
j: R = CH Ph, R' = Et
2
TM
Scheme 1. Synthesis of BoPhoz phosphine-amide ligands 1.
The reaction characteristics of the palladium complexes
of these ligands were explored using acetamide 1a and
propionamide 1b as ligands for the reaction of 1,3-
diphenylpropenyl acetate 3 with dimethyl malonate, the
standard test reaction for asymmetric allylation chem-
istry. The initial conditions utilized THF as solvent
and potassium acetate as base in the presence of
*
0
Corresponding author. Tel.: +1-423-229-8105; fax: +1-423-224-7582;
e-mail: nwboaz@eastman.com
957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.04.043

2152
N. W. Boaz et al. / Tetrahedron: Asymmetry 15 (2004) 2151–2154
N,O-bis(trimethylsilyl)trifluoroacetamide
(BSTFA).
afforded very poor enantioselectivity (entry 4) while the
N-benzoyl species 1d showed poor reactivity, although
affording high enantioselectivity (entry 6). The Boc
carbamate 1e afforded no reaction.
This latter reagent was used for convenience, and sub-
sequent reactions indicated identical results with the
more commonly used N,O-bis(trimethylsilyl)acetamide
(
BSA). Initial results were promising, with the prop-
ionamide 1b affording slightly higher enantioselectivity
compared to the acetamide 1a.
Previously reported asymmetric hydrogenation work
using phosphine-aminophosphine ligands based on
structure 1 indicated a limited influence of the R groups
4
The effects of the reaction conditions were examined
using the palladium complex of the N-propionyl species
on the reaction characteristics of the ligand. That was
not the case for allylic alkylation, as variation of the R
group had a profound effect upon the reaction and
perhaps afforded some insight into the nature of the
catalysts based on ligands 1. As indicated in Table 3,
adding steric bulk around the nitrogen resulted in ex-
tremely slow reactions, affording poor conversion even
after extended reaction times with high catalyst load-
ings. The enantioselectivities of these reactions were also
generally poor. It is quite intriguing that most of these
N-alkyl compounds afforded the product 4 with the
opposite R configuration in contrast to the N–H ligands.
The lone exception was ligand 1f, which showed a
curious change in selectivity with reaction duration. At
short reaction times the S enantiomer of 4 predomi-
nated, albeit with low enantioselectivity (entries 1 and
2). However, at longer reaction times the R enantiomer
became the major product (see entries 2 and 3, which
were the same run at differing reaction times), suggesting
that there may be more than one active catalyst species
present.
6
1
b. These results are shown in Table 1, and indicate
that both the solvent and the base employed can have an
effect on the course of the reaction. An initial screen
indicated that TBME (tert-butyl methyl ether) was the
best solvent for this reaction, although good results were
also obtained with THF and toluene. Poor reactivity
was observed with dichloromethane, diethoxymethane
(
DEM), and tetrachloroethylene (TCE). Lithium car-
bonate, potassium acetate, and sodium acetate all
afforded good enantioselectivity while lithium acetate
afforded decidedly poorer results. Sodium carbonate
and potassium carbonate afforded high enantioselectiv-
ities but a reduced reaction rate. The rationale behind
these results is unclear, and illustrates the subtleties
inherent in this complex multi-component reaction.
The ligand 1 affords ample opportunity for tuning the
reactivity and selectivity of the catalyst by variation of
0
both the R substituent and the R of the acyl group on
the nitrogen. We initially investigated the variation of
the acyl group of the primary amide. The results shown
in Table 2 indicate that the N-propionyl group is
decidedly superior for this transformation, affording
The generality of the palladium-catalyzed allylic alkyl-
ation reactions utilizing ligand 1b was investigated by
examining the reaction of dimethyl malonate with cy-
clohex-2-enyl acetate. This substrate has decidedly dif-
ferent steric demands compared to 3, and afforded a
more moderate 83% ee under the best conditions
2 3
under the optimum conditions (TBME, Li CO ,
BSTFA) 100% conversion with 98.8% ee for the S
enantiomer of 4 (entry 3). Larger groups afforded sig-
nificantly poorer results. The N-pivaloyl species 1c
(2 mol % catalyst, Li
2
CO
3
, TBME).
a
Table 1. Optimization using ligand 1b
dimethyl malonate
([allyl]PdCl)2
Ligand 1b
Ph
Ph
Ph
Ph
OAc
BSTFA
base
H COOC
3
COOCH3
solvent, RT
3
S-4
b
c
Entry
Solvent
Base
Time (h)
Conversion (%)
Ee (%)
Yield (%)
1
2
3
4
5
6
7
8
9
TBME
THF
Toluene
Li
Li
Li
Li
Li
Li
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
3
15
18
18
18
18
18
15
15
15
40
40
100
99.5
99.3
54.2
3.0
98.8
97.2
94.4
97.4
nd
88
88
94
nd
nd
nd
nd
87
86
84
81
3
3
3
3
3
2 2
CH Cl
DEM
TCE
2.5
nd
TBME
TBME
TBME
TBME
TBME
KOAc
LiOAc
>99
>99
90.7
100
100
95.4
73.2
96.2
96.6
95.8
NaOAc
Na
1
1
0
1
2 3
CO
K
2
CO
3
a
Reactions run with 2 mol % catalyst for the time indicated.
Enantiomeric excess of 4 was determined by chiral HPLC using a 250 · 4.6 mm Chiralcel OD-H column (Chiral Technologies), mobile phase 98:2
hexane–isopropanol, flow rate 1 mL/min, k ¼ 254 nm.
b
c
2
Yield of isolated product after flash chromatography (SiO , 9:1 heptane–ethyl acetate).

N. W. Boaz et al. / Tetrahedron: Asymmetry 15 (2004) 2151–2154
2153
0
a
Table 2. Variation of acyl R of ligand 1
dimethyl malonate
(
[allyl]PdCl)2
Ligand 1
Ph
Ph
OAc
Ph
Ph
BSTFA
base
H COOC
COOCH3
3
TBME
RT, 15 h
3
S-4
0
Entry
Ligand
R
Base
Conversion (%)
Ee (%)
1
2
3
4
1a
1b
1b
1c
1d
1d
1e
CH
Et
3
KOAc
KOAc
Li CO
99.1
>99
100
97.4
26.9
95.8
0
96.6
95.4
98.8
4.8
Et
2
3
t-Bu
Ph
KOAc
KOAc
b
5
24.8
93.1
Nd
c
6
d
Ph
t
Li
Li
2
CO
CO
3
7
O Bu
2
3
a
b
c
Reaction run with 2 mol % catalyst for 15 h except where indicated.
Reaction run for 38 h.
Reaction run with 10 mol % catalyst in THF for 41 h.
Reaction run with 10 mol % catalyst for 17 h.
d
a
Table 3. Variation of R group of ligand 1
dimethyl malonate
(
[allyl]PdCl)2
Ligand 1
Ph
Ph
OAc
Ph
*
Ph
BSTFA
base
H COOC
COOCH3
3
THF
RT, 17 h
3
4
0
Entry
Ligand
R
R
Base
Conversion (%)
Ee (%)
b
1
1f
1f
1f
1g
1h
1i
CH
CH
CH
CH
Ph
3
3
3
3
CH
CH
CH
Et
3
3
3
KOAc
16.7
3.8
9.6
12.3
1.8
0
10.8 S
17.3 S
16.1 R
38.4 R
52.7 R
nd
2
Li
2
Li
2
Li
2
Li
2
Li
2
Li
2
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
c
3
4
5
6
7
Et
CH
CH
2
Ph
Ph
CH
Et
3
1j
2
0
nd
a
b
c
Reactions run with 10 mol % catalyst for 17 h except where indicated.
Reaction run with 2 mol % catalyst in CH
Reaction run for 41 h.
2 2
Cl for 36 h.
Previous work has indicated that phosphine-amide
species ligate to the palladium through the phosphorus
dence for the preferred binding mode of ligands 1. The
high enantioselectivity and reactivity of the N–H ligands
coupled with the poor reactivity and inverse selectivity
of the N-alkyl amides (which are more sterically hin-
dered around the nitrogen), implies a nitrogen–phos-
phorus binding mode. In addition, the selectivity
inversion at extended reaction times observed for ligand
1f, the least sterically encumbered of the N-alkyl species,
suggests that a slow interconversion between two cata-
lytically active species, perhaps a phosphorus–nitrogen
ligated species converting to a phosphorus–oxygen
ligated species, may be occurring during the course of
the reaction. The monodentate nature of the crystallized
precatalyst also implies that the amide is a weak binding
donor, which could facilitate the interconversion of N-
ligated and O-ligated complexes. Additional support for
the phosphorus–nitrogen ligation for ligands 1a–1d in-
cludes the fact that the palladium complex of unsubsti-
tuted amine 2 (R ¼ H) shows good reactivity (100%
conversion) and fairly high enantioselectivity (89% ee S)
for the reaction of 3 with dimethyl malonate.
2
;3
and the amide oxygen. The ligands used in those
investigations, however, are structurally disposed to
afford a six-membered palladacycle. It is yet unknown
how ligands 1 interact with the palladium, whether via
a phosphorus–nitrogen six-membered palladacycle or a
phosphorus–oxygen
eight-membered
palladacycle.
Absolute determination of the binding mode could best
be answered by X-ray crystallographic analysis. Unfor-
tunately, most of the complexes investigated exhibited
poor crystallization behavior. The sole exception was
the combination of ligand 1b and allylpalladium chlo-
ride dimer, which afforded suitable crystals from THF
solution. Unfortunately, the crystal structure indicated
that this material was a monodentate phosphorus-
ligated palladium(II) chloride species, which at best can
be considered a pre-catalytic complex and is not par-
ticularly relevant to understanding the reactivity and
enantioselectivity of these catalysts. In contrast, the
results of the allylation reactions provide indirect evi-

2154
N. W. Boaz et al. / Tetrahedron: Asymmetry 15 (2004) 2151–2154
Thus we have demonstrated that a new class of phos-
phine-amide ligands based on a diphenylphosphino-
ferrocenylethylamine backbone can afford exceedingly
high enantioselectivities for palladium-catalyzed allylic
alkylation reactions. The nature of the ligation is not yet
proven, but the evidence suggests that productive
binding occurs through the phosphorus and the nitrogen
of the amide, at variance with other phosphine-amides,
which involve phosphorus–amide oxygen ligation.
with argon for 15 min. Triethylamine (240 mL, 1.74 mmol,
.5 equiv) was added followed by propionic anhydride
178 mL, 1.39 mmol, 1.2 equiv). Solid was noted after
5 min. The reaction mixture was allowed to warm to
ambient temperature overnight at which point TLC anal-
ysis indicated no 2 present (1:2 heptane–ethyl acetate).
Water (5 mL) and heptane (10 mL) were added and the
mixture was stirred for 10 min at ambient temperature. The
precipitate was collected by filtration, washed with water
1
(
1
and heptane, and dried to afford 0.40 g (73%) of 1b, mp
1
1
7
57–158 ꢁC. H NMR (CDCl
3
) d 7.54–7.48 (m, 2H); 7.38–
.35 (m, 3H); 7.26–7.16 (m, 5H); 5.887 (br s, 1H); 5.178
Acknowledgements
(
m(5), 1H, J ¼ 6:87 Hz); 4.462 (br s, 1H); 4.296 (t, 1H,
J ¼ 2:47 Hz); 4.015 (s, 5H); 3.787 (m, 1H); 1.79–1.52 (m,
The authors wish to thank Amy K. Farthing for
experimental assistance and Professor Robin D. Rogers
and Scott Griffin for X-ray crystallographic analysis.
2H); 1.371 (d, 3H, J ¼ 6:87 Hz); 0.903 (t, 3H, J ¼ 7:69 Hz).
1
3
C NMR (CDCl
J
3
) d 171.7 (s); 139.9 (d, JC–P ¼ 9 Hz); 137.0
C–P
(
d,
C–P ¼ 8 Hz); 135.1 (d,
J
¼
21 Hz); 132.6 (d,
J
1
C–P ¼ 18 Hz); 129.4 (s); 128.3 (d, JC–P ¼ 9 Hz); 128.3 (s);
28.2 (s); 95.5 (d, JC–P ¼ 23 Hz); 74.7 (d, JC–P ¼ 11 Hz); 72.2
References and notes
(s); 70.5 (d, JC–P ¼ 4 Hz); 70.0 (s); 69.3 (s); 44.8 (d,
C–P ¼ 5 Hz); 29.3 (s); 21.9 (s); 9.7 (s). FDMS: m=z 469
J
þ
þ
1
. For reviews, see: (a) Trost, B. M.; Crawley, M. L. Chem.
Rev. 2003, 103, 2921–2943; (b) Trost, B. M.; Chulbom, L.
In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.;
VCH: New York, 2000; pp 593–640; (c) Pfaltz, A.; Lautens,
M. In Comprehensive Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
Vol. 2, pp 833–884; (d) Trost, B. M. Acc. Chem. Res. 1996,
(M ). HRMS calcd for C27
found: 470.1345. Anal. Calcd for C27
H, 6.01; N, 2.98. Found: C, 69.04; H, 6.08; N, 2.97.
H
29FeNOP (M+H) : 470.1336,
H28FeNOP: C, 69.10;
2
3
½aꢀ ¼ ꢁ308 (c 1.05, methanol).
D
6. A typical allylation procedure is as follows: Allylpalladium
chloride dimer (3.7 mg, 0.01 mmol, 0.01 equiv), ligand 1b
(11.3 mg, 0.024 mmol, 0.024 equiv), 1,3-diphenylpropenyl
acetate 3 (252 mg, 1.0 equiv), and lithium carbonate (2 mg,
0.027 mmol, 0.027 equiv) were combined and 6 mL of
TBME was added. The mixture was stirred at ambient
temperature for 15 min. Dimethyl malonate (0.34 mL,
3.0 mmol, 3.0 equiv) and BSTFA (0.74 mmol, 3.0 mmol,
3.0 equiv) were added and the reaction mixture was stirred
at ambient temperature for 15 h, at which point chiral
HPLC analysis indicated 100% conversion and 98.8% ee for
S-4. The volatiles were stripped and the residue was flash-
chromatographed on silica gel and eluted with 1:9 ethyl
29, 355–364.
2
3
. (a) Claydeen, J.; Johnson, P.; Pink, J.; Helliwell, M. J. Org.
Chem. 2000, 65, 7033–7040; (b) Mino, T.; Kashihara, K.;
Yamashita, M. Tetrahedron: Asymmetry 2001, 12, 287–291;
(
c) Gilbertson, S. R.; Lan, P. Org. Lett. 2001, 3, 2237–2240;
d) Chen, Y.; Smith, M. D.; Shimizu, K. D. Tetrahedron
(
Lett. 2001, 42, 7185–7187.
. There are reports of multi-dentate ligands, which may
function as phosphine-amides: (a) Trost, B. M.; Breit, B.;
Organ, M. G. Tetrahedron Lett. 1994, 35, 5817–5820; (b)
Butts, C. P.; Crosby, J.; Lloyd-Jones, G. C.; Stephen, S. C.
J. Chem Soc., Chem. Commun. 1999, 1707–1708; (c) Kim,
Y. K.; Lee, S. J.; Ahn, K. H. J. Org. Chem. 2000, 65, 7807–
1
acetate–heptane to afford 285 mg of (S)-4 (88%). H NMR
(CDCl
3
) d 7.34–7.19 (m, 5H); 6.478 (d, 1H, J ¼ 15:93 Hz);
6.304 (dd, 1H, J ¼ 8:52, 15.66 Hz); 4.257 (dd, 1H, J ¼ 8:52,
10.99 Hz); 3.950 (d, 1H, J ¼ 10:99 Hz); 3.699 (s, 3H); 3.514
(s, 3H). Chiral HPLC (Chiralcel OD-H column [Chiral
Technologies], mobile phase 98:2 hexane–isopropanol,
7813.
4
. Boaz, N. W.; Debenham, S. D.; Mackenzie, E. B.; Large, S.
E. Org. Lett. 2002, 4, 2421–2424.
5
. A typical procedure for the preparation of ligand 1b is as
follows: Amine 2 (R ¼ H) (480 mg, 1.16 mmol) was dis-
solved in 5 mL of toluene, cooled in ice-water, and purged
1 mL/min, k ¼ 254 nm): t
R
13.0, 13.6 min (3); t
R
15.2 min
2
3
[(R)-4]; t
R
16.2 min [(S)-4]. ½aꢀ ¼ ꢁ17:6 (c 1.68, ethanol),
D
indicating (S)-enantiomer for 4.
2
b