Chiral phosphinooxazolines with a pentamethylferrocene backbone - Synthesis and use as ligands in asymmetric catalysis

Article abstract of DOI:10.1021/jo0526136

Novel phosphinooxazolines, containing a unit of central and a unit of planar chirality in a matched case combination, have been successfully tested in the Pd-catalyzed asymmetric allylic substitution with cycloalkenyl acetates as substrates.

Full text of DOI:10.1021/jo0526136

Chiral Phosphinooxazolines with a Pentamethylferrocene
BackbonesSynthesis and Use as Ligands in Asymmetric Catalysis
Felix M. Geisler and Gu¨nter Helmchen*
Organisch-Chemisches Institut, UniVersita¨t Heidelberg, Im Neuenheimer Feld 270,
69120 Heidelberg, Germany
g.helmchen@urz.uni-heidelberg.de
ReceiVed December 20, 2005
Novel phosphinooxazolines, containing a unit of central and a unit of planar chirality in a matched case
combination, have been successfully tested in the Pd-catalyzed asymmetric allylic substitution with
cycloalkenyl acetates as substrates.
Introduction
Pd-catalyzed asymmetric allylic substitutions1 have been
successfully applied in organic synthesis.2 Numerous chiral
ligands have been tested, however, only a few have been
found that induce an enantiomeric excess of >90% in the
reaction with a cyclic substrate.3 Only a few of these ligands
have been applied in syntheses of biologically active compounds.
These are the ligands A and B, developed in our group and
Trost’s ligand C, which is a member of a large class of ligands
(Figure 1).3a-c
* To whom correspondence should be addressed. Phone: +49 6221 548401.
Fax: +49 6221 544205.
(1) (a) Trost, B. M.; Lee, C. Asymmetric Allylic Alkylation Reactions.
In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH:
New York, 2000; pp 593-649. (b) Trost, B. M.; van Vranken, D. L. Chem.
ReV. 1996, 96, 395-422. (c) Helmchen, G. J. Organomet. Chem. 1999,
576, 203-215. (d) Helmchen, G.; Steinhagen, H.; Kudis, S. Enantioselective
Catalysis of Allylic Substitutions with Palladium Complexes of Phosphi-
nooxazolines. In Transition Metal Catalysed Reactions - Chemistry for
the 21st Century Monographs; Murahashi, S., Davies, S. G., Eds.;
Blackwell: Oxford, 1999; pp 241-260. (e) Pfaltz, A.; Lautens, M. Allylic
Substitution Reactions. In ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Heidelberg, 1999; pp 833-
886.
FIGURE 1. Chiral ligands useful in Pd-catalyzed allylic substitutions
at cyclic substrates.
The basis of the design of ligands A is conformational
confinement of the aryl groups at P by the Mn(CO)3 moiety
via a steric effect. With ligand A1, containing a PPh2 group,
moderate enantioselectivities were achieved; the ligand A2,
(2) (a) Kudis, S.; Helmchen, G. Tetrahedron 1998, 54, 10449. (b)
Schleich, S.; Helmchen, G. Eur. J. Org. Chem. 1999, 2515, 5-2521. (c)
Bergner, E.; Helmchen, G. Eur. J. Org. Chem. 2000, 419-423. (d) Bergner,
E. J.; Helmchen, G. J. Org. Chem. 2000, 65, 5072-5074. (e) Ernst, M.;
Helmchen, G. Synthesis 2002, 14, 1953-1955. (f) Ernst, M.; Helmchen,
G. Angew. Chem. 2002, 114, 4231-4234; Angew. Chem., Int. Ed. 2002,
41, 4054-4056. (g) Seemann, M.; Scho¨ller, M.; Kudis, S.; Helmchen, G.
Eur. J. Org. Chem. 2003, 2122-2127. (h) Paradies, G.; Ernst, M.;
Helmchen, G. Pure Appl. Chem. 2004, 76, 495-506. (i) Trost, B. M.;
Crawley, M. L. Chem. ReV. 2003, 103, 2921-2943. (k) Graening, T.;
Schmalz, H.-G. Angew. Chem. 2003, 115, 2684-2688; Angew. Chem., Int.
Ed. 2003, 42, 2580-2584.
(3) (a) Kudis, S.; Helmchen, G. Angew. Chem. 1998, 110, 3210-3212;
Angew. Chem., Int. Ed. 1998, 37, 3047-3050. (b) Knu¨hl, G.; Sennhenn,
P.; Helmchen, G. J. Chem. Soc., Chem. Commun. 1995, 1845-1846. (c)
Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089-4090. (d)
Gilbertson, S. R.; Xie, D. Angew. Chem. 1999, 111, 2915-2918; Angew.
Chem., Int. Ed. 1999, 38, 2750-2752. (e) Evans, D. A.; Campos, K. R.;
Tedrow, J. S.; Michael, F. E.; Gagne, M. R. J. Org. Chem. 1999, 64, 2994-
2995. (f) Evans, D. A.; Campos, K. R.; Tedrow, J. S.; Michael, F. E.; Gagne,
M. R. J. Am. Chem. Soc. 2000, 122, 7905-7920. (g) Uozumi, Y.; Shibatomi,
K. J. Am. Chem. Soc. 2001, 123, 2919-2920. (h) Pamies, O.; Dieguez,
M.; Claver, C. J. Am. Chem. Soc. 2005, 127, 3646-3647.
10.1021/jo0526136 CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/23/2006
2486
J. Org. Chem. 2006, 71, 2486-2492

Synthesis of Chiral Phosphinooxazoline Ligands
SCHEME 1
FIGURE 2. Stereoselective directed lithiation.
SCHEME 2
containing an o-biphenylyl group at P, induced an excellent
enantiomeric excess of >90% ee. We wondered whether a
similar effect would be obtained upon replacement of the
cymantrene by a pentamethylferrocene unit, that is, with ligands
of the type D. Ligands D are generally more electron rich than
ligands A; it was hoped that the large steric bulk of the
pentamethylcyclopentadienyl (Cp*) moiety might give rise to
high levels of enantioselection even for ligands D with a
nonstereogenic phosphino group, for example PR2R3 ) PPh2.
Ligands with a planar-chiral pentamethylferrocene unit have
previously been prepared by Fu and co-workers and Togni and
co-workers.4
Ligands with a planar-chiral ferrocene unit,5 including phos-
phinooxazolines with a ferrocene backbone, have been exten-
sively studied, and their synthesis is well-established. The key
step in the preparation of the phosphinoxazolines is directed
lithiation of a chiral oxazoline.6 This reaction usually proceeds
with a high degree of diastereoselection and was also applied
here.
worked out, involving aminolysis of the ester 1 (Scheme 1),
that eventually allowed the preparation of amides 2a-d (Scheme
2) from readily available starting materials in satisfactory yields.
The requisite pentamethylferrocene carboxylic acid methyl
ester 1 was prepared by reaction of FeCl2 with 1.1 equiv of
lithium pentamethyl cyclopentadienide and 1.0 equiv of sodium
methoxycarbonylcyclopentadienide,9 using a procedure devel-
oped for the synthesis of pentasubstituted acylferrocenes10
(Scheme 1). Decamethylferrocene, produced in small amount
as a side product, could be easily removed by filtrative column
chromatography. The preparation of 1 has been carried out on
a 200 mmol scale.
Reaction of the ester 1 with aluminum amides11 in refluxing
toluene furnished the amides 2a-d in yields of 84-94%
(Scheme 1). Lower yields (41-72%) were obtained with lithium
or sodium amides or with the use of solvents with a boiling
point lower than that of toluene. The amides 2 were transformed
into the oxazolines 3 by treatment with p-TsCl/triethylamine
and a catalytic amount of DMAP (Scheme 2).
As mentioned above, the directed metalation of ferrocenyl-
oxazolines is an established reaction and allows electrophiles
to be introduced conveniently.6 The steric course anticipated
for reactions with oxazolines 3a-d is described in Figure 2.
Nevertheless, there was no information available on the
metalation of pentamethylferrocenyloxazolines. Accordingly,
suitable reaction conditions had to be worked out for compounds
3a-d (Table 1).
Results and Discussion
At the early stage of the project, pentamethylferrocene car-
boxylic acid amides 2 (Scheme 1) were prepared from penta-
methylferrocene via pentamethylferrocene carboxylic acid,
which was prepared according to a procedure of Bildstein et
al.7 The acid was treated with oxalyl chloride to give the acid
chloride, and this was reacted with the amino alcohol. The yields
were generally poor.8 As a consequence, a new route was
(4) (a) Abbenhuis, H. C. L.; Burckhardt, U.; Gramlich, V.; Togni, A.
Organometallics 1994, 13, 4481-4493. (b) Abbenhuis, H. C. L.; Burckhardt,
U.; Gramlich, V.; Martelletti, A.; Spencer, J.; Steiner, I.; Togni, A.
Organometallics 1996, 15, 1614-1621. (c) Ruble, J. C.; Fu, G. C. J. Org.
Chem. 1996, 61, 7230-7231. (d) Liang, J.; Ruble, J. C.; Fu, G. C. J. Org.
Chem. 1998, 63, 3154-3155. (e) Tao, B.; Lo, M. M.-C.; Fu, G. C. J. Am.
Chem. Soc. 2001, 123, 353-354. (f) Tao, B.; Fu, G. C. Angew. Chem.
2002, 114, 4048-4050; Angew. Chem., Int. Ed. 2002, 41, 3892-3894.
(5) (a) Togni, A. Angew. Chem. 1996, 108, 1581-1583; Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1475-1477. (b) Hayashi, T. Asymmetric Catalysis
with Chiral Ferrocenylphosphine Ligands. In Ferrocenes; Togni, A.,
Hayashi, T., Eds.; VCH: Weinheim, 1998; pp 105-142. (c) Dai, L.-X.;
Tu, T.; You, S.-L.; Deng, W.-P.; Hou, X.-L. Acc. Chem. Res. 2003, 36,
659-667. (d) Sutcliffe, O. B.; Bryce, M. R. Tetrahedron: Asymmetry 2003,
14, 2297-2325. (e) Atkinson, R. C. J.; Gibson, V. C.; Long, N. J. Chem.
Soc. ReV. 2004, 33, 313-328.
Preliminary experiments quickly revealed that t-BuLi was not
suited as a base because of metalation of the methyl groups of
the Cp* moiety. Similarly, reaction with s-BuLi/Et2O followed
by quenching with a chlorophosphane gave poor results (Table
1, entry 1). Better results were generally achieved with s-BuLi/
TMEDA.
(6) (a) Richards, C. J.; Damalidis, T.; Hibbs, D. E.; Hursthouse, M. B.
Synlett 1995, 74-76. (b) Sammakia, T.; Latham, H. A.; Schaad, D. R. J.
Org. Chem. 1995, 60, 10-11. (c) Nishibayashi, Y.; Uemura, S. Synlett 1995,
79-81. (d) Sammakia, T.; Latham, H. A. J. Org. Chem. 1995, 60, 6002-
6003. (e) Sammakia, T.; Latham, H. A. J. Org. Chem. 1996, 61, 1629-
1635. (f) Richards, C. J.; Mulvaney, A. W. Tetrahedron: Asymmetry 1996,
7, 1419-1430.
(8) Meyer, O. Ph.D. Dissertation, Universitaet Heidelberg, Heidelberg,
Germany, 2003.
(9) Hart, W. P.; Macomber, D. W.; Rausch, M. D. J. Am. Chem. Soc.
1980, 102, 1196.
(10) Norinder, J.; Cotton, H. K.; Ba¨ckvall, J.-E. J. Org. Chem. 2002, 67
(25), 9096-9098.
(11) (a) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
4171. (b) Ahn, K. H.; Cho, C.-W.; Baek, H.-H.; Park, J.; Lee, S. J. Org.
Chem. 1996, 61, 4937-4943.
(7) Bildstein, B.; Hradsky, A.; Kopacka, H.; Malleier, R.; Ongania, K.-
H. J. Organomet. Chem. 1997, 540, 127-145.
J. Org. Chem, Vol. 71, No. 6, 2006 2487

Geisler and Helmchen
TABLE 1. Synthesis of L1-L5 from Oxazolines 3a-3d, According
Pd complexes containing diastereomerically pure L2 (see
below).
to Scheme 4
equiv of equiv of
s-BuLi TMEDA electrophile
conv.a yieldb
Ligands L1-L5 were tested in the asymmetric allylic
alkylation of cyclic substrates 4 with dimethyl sodiomalonate
(see Scheme 5 and Table 2). The latter was generated from
dimethyl malonate either by a reaction with NaH or in situ by
an addition of N,O-bistrimethylsilyl acetamide (BSA)/sodium
acetate to the reaction mixture. In all reactions, the products
with the (R) configuration were preferentially formed.12 This
was also found for allylic substitutions promoted by ligands
A1 and A2 (cf. Figure 1, Table 2, entries 20-22).
entry
R
(%)
(%)
dec
1
2
3
t-Bu
t-Bu
t-Bu
1.1
1.1
1.1d
1.2
1.1
1.3
1.3
1.3
1.3
1.3
0
PPh2Cl
PPh2Cl
PPh2Cl
PPh2Cl
PPh2Cl
PPh2Cl
PPh2Cl
PPh2Cl
P(t-Bu)2Cl
(PhS)2
<5
31
23
42
38
n.d.
n.d.
59
n.d.
52
n.d.
n.d.
n.d.
n.d.
n.d.
40
46
38
37
42
n.d.
>99
92
63
>99
98
>99
>99
>99
>99
1.1
1.1
1.2
1.1
1.3
1.3
1.3
1.3
1.3
4e Bn
5
6
7
8
9
i-Pr
Bn
i-Pr
t-Bu
t-Bu
t-Bu
10
SCHEME 5
a Determined by 1H NMR. b Determined by column chromatography.
c Determined by 1H NMR or 31P NMR. d Metalation with n-BuLi. e n-
Hexane was used as solvent.
SCHEME 3
SCHEME 4
Substrate 4b was used for the optimization of reaction
conditions and the assessment of ligands (Table 2, entries 1-11)
because of the particularly convenient determination of the
enantiomeric excess of the substitution product 5b. The best
results were obtained with ligand L2 in conjunction with the
BSA method using THF or dioxane as solvent (Table 2, entries
4 and 9). Similar results were obtained with DMF as solvent;
however, reactions were slower than with THF. While results
with L1 and L3 were acceptable, those with L4 and L5 were
not. Typical for many Pd-catalyzed allylic substitutions using
N,S-chelate ligands,13 reactions promoted by L5 displayed low
yield because of the precipitation of metallic palladium.
Typical for most Pd-catalyzed allylic substitutions of cyclic
substrates,3 reactions of the seven-membered substrate 4c
displayed the highest level of selectivity (Table 2, entry 12).
Cyclopentenyl acetate 4a, expectedly,3 was the most reactive
substrate (Table 2, entries 13-19). This allowed the lowering
of the reaction temperature to -30 °C; at this temperature,
essentially quantitative yield and an enantiomeric excess of 92%
was achieved (Table 2, entries 18 and 19).
The results achieved with ligand L2 are surprisingly good in
comparison with those previously obtained with the ligand A1
(cf. Table 2, entry 20). They are indeed similar to those obtained
with the more complicated ligand A2 containing a stereogenic
phosphorus center. The configuration of the products (R) are
as expected for reactions proceeding via an exo-[(π-allyl)-
(PHOX)] complex (cf. Figure 5), with a preferred addition of
the nucleophile at the allylic C trans to phosphorus.
To shed further light on the intermediary π-allyl complexes,
the complexes K1 and K2 were prepared (Scheme 6). These
were obtained by a reaction of the commercially available
complex 6a and complex 6b14 with L2, followed by an anion
exchange by the addition of AgSbF6. In CDCl3 solution, K1
consisted of a mixture of two η3-allyl complexes in a ratio of
77:23, and K2 consisted of two complexes in a ratio of 99:1
(31P NMR).
To assess the efficiency of the metalation step, lithiation of
the oxazoline 3b was carried out at -78, -40, and 0 °C with
1.3 equiv of s-BuLi/TMEDA, followed by quenching with D2O
after 1 h (Scheme 3). At -78 °C, 74% (pR)-monodeuteration
occurred. The reaction at -40 °C gave rise to 95% deuterium
in the (pR) and 14% in the (pS) position. After the metalation
at 0 °C, 59% of the deuterium was found in the (pR), 19% in
the (pS), and 14% in the â position. Accordingly, the metalation
as well as the subsequent reaction with an electrophile have to
be carried out at a temperature well below -40 °C.
In the reaction with Ph2PCl and (PhS)2, significant conver-
sion was only achieved after metalation with s-BuLi/TMEDA.
The diastereomeric purity of the coupling products was ex-
cellent: >99% for the formation of L1, L2, L4, and L5 (cf.
Table 1, entries 2, 5 and 7-10). In the case of oxazoline 3c,
the dihydrooxazolyl group was metalated at the dNsCH
position, according to the 1H NMR spectrum of the crude
product. With n-hexane as solvent, slightly improved yield
but very low diastereoselectivity was obtained (Table 1,
entry 4).
(12) Characterization of known compounds 5a, 5b, and 5c: (a) Trost,
B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089-4090. (b) Sennhenn,
P.; Gabler, B.; Helmchen, G. Tetrahedron Lett. 1994, 35, 8595-8598.
(13) (a) Sprinz, J.; Kiefer, M.; Helmchen, G.; Reggelin, M.; Huttner,
G.; Walter, O.; Zsolnai, L. Tetrahedon Lett. 1994, 35, 1523-1526. (b)
Dawson, M. J.; Frost, C. G.; Martin, C. J.; Williams, M. J. M. Tetrahedron
Lett. 1993, 34, 7793-7796.
The relative configurations of the products L1-L5, as given
in Scheme 4, is assumed to be the same as those of the
2-substituted ferrocenyloxazolines, prepared in the same way
by Richards and Sammakia.6 In the case of L2, this assumption
was proven correct by the X-ray crystal analyses of two cationic
(14) Trost, B. M.; Strege, P. E.; Weber, L.; Fullerton, T. J.; Dietsche, T.
J. J. Am. Chem. Soc. 1978, 100, 3407-3215.
2488 J. Org. Chem., Vol. 71, No. 6, 2006

Synthesis of Chiral Phosphinooxazoline Ligands
TABLE 2. Allylic Alkylation of Cyclic Substrates 4a-c, According to Scheme 5
temp
(°C)
time
(h)
conv.b
(%)
yieldc
(%)
ee
(%)
entry
n
liganda
solvent
base
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20i
21i
22i
6
6
6
6
6
6
6
6
6
6
6
7
5
5
5
5
5
5
5
6
6
6
L1d
L2e
L3d
L2e
L2e
L2e
L2e
L2e
L2e
L4d
L5e
L2d
L2e
L2e
L2e
L2e
L2e
L2e
L2e
A1e
A2e
A2e
THF
THF
THF
THF
DMF
DMF
DMF
CH2Cl2
dioxane
THF
THF
THF
THF
DMF
THF
THF
THF
THF
DMF
THF
THF
DMF
NaH
NaH
NaH
BSA
NaH
NaH
BSA
BSA
BSA
BSA
BSA
BSA
NaH
NaH
BSA
BSA
BSA
BSA
NaH
NaH
NaH
NaH
20
20
20
20
20
0
20
20
20
20
20
20
20
20
20
0
1.5
2
4
5
2
16
5
4
5
5
16
3
<0.1
<0.1
<0.1
<0.1
4
16
48
0.2
0.2
0.6
>99
>99
92
98
99
>99
>99
>99
86
97
<5
>99
>99
>99
>99
>99
>99
>99
>99
n.d.
n.d.
n.d.
n.d.
94
n.d.
92
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
93
n.d.
95
n.d.
96
97
96
73 (R)f
81 (R)f
66 (R)f
84 (R)f
81 (R)f
84 (R)f
80 (R)f
78 (R)f
85 (R)f
15 (R)f
n.d.
94 (R)g
64 (R)h
79 (R)h
83 (R)h
88 (R)h
91 (R)h
92 (R)h
92 (R)h
31 (R)f
85 (R)f
87 (R)f
-20
-30
-30
20
20
20
97
97
95
97
a Molar ratio of ligand/Pd ) 1.1:1. b Determined by GC: Chrompack permethyl â-CD (see footnotes f and g below). c Isolated yield after column
chromatography. d 4.4 mol % of ligand. e 1.1 mol % of ligand. f Determination by GC: Chrompack permethyl â-CD, 110 °C, tR [(S)-5b] ) 44.5 min, tR
[(R)-5b] ) 45.8 min. g Determination by GC: Chrompack permethyl â-CD, 100 °C, tR [(R)-5c] ) 135.6 min, tR [(S)-5c] ) 141.4 min. h Determined via an
iodolactone as the derivative, as described in ref 2g. i Data taken from ref 3a.
SCHEME 6
In the case of K1, the conformation of the PHOX ligand relative
to the coordination plane [N,Pd,P], mainly determined by the
angle ø, the angle between the ‘best-fit’ plane through the ligand
atoms N, C2, C6, C7, and P and the plane [N,Pd,P] (cf. Figure
4), is similar to that of the corresponding Pd complex of A2.
However, the angle ø of complex K2 is extremely small, that
is, this complex possesses an unusually flat backbone. This is
immediately apparent upon inspection of the model displayed
in Figure 6. A consequence is stronger shielding of the half
space of the coordination plane containing the tert-butyl and
the PhRe group. This is in accord with the very pronounced
preference of the exo isomer in the case of K2. Thus, the
structural features support the view that the preferred enantiomer
arises by the addition of the nucleophile at the allylic carbon
trans to P of the exo-π-allyl complex.
Crystals suitable for X-ray crystal structure determination
were grown by slow diffusion (rt) of diethyl ether into the
solution of the complex in CH2Cl2.15 In the case of K1, the
crystal contained two exo-complexes in 1:1 ratio that displayed
small differences in the positions of the Ph and the Cp* groups.
In the case of K2 only the exo-complex was found in the crystal
(Figures 3 and 4).
Characteristic structural data is presented in the Supporting
Information and Figures 4 and 6. Typical for all (π-allyl)-
(PHOX)Pd complexes is the long bond between Pd and the
allylic terminus (C3a) in a trans position relative to phosphorus
(bond lengths Pd-C3a ) 2.262 Å and Pd-C1a ) 2.128 Å for
K2), that is, the bond broken in the allylic substitution to give
the product configuration that is observed (R) (cf. Figure 5).16
In conclusion, sterically highly demanding planar chiral
PHOX ligands with a pentamethylferrocene backbone have been
synthesized and used as ligands in Pd-catalyzed asymmetric
allylic alkylations of cyclic substrates. With the ligand L2,
excellent yield and enantioselectivity were achieved at a low
load of the catalyst.
Experimental Section
Methyl 1′,2′,3′,4′,5′-Pentamethylferrocenecarboxylate (1).
A: A suspension of FeCl2 (10.4 g, 82.0 mmol) in THF (800 mL)
was vigorously stirred in the dark for 5 h.
B: A mixture of sodium cyclopentadienide (45.0 mL of a 2.0
M solution in THF, 90.0 mmol) and dimethyl carbonate (13.4 mL,
148.8 mmol) in THF (80 mL) was heated at reflux for 4 h.
C: For the preparation of lithium pentamethylcyclopentadienide,
n-BuLi (56.7 mL of a 1.6 M solution in n-hexane, 90.0 mmol) was
added dropwise to a cooled (-78 °C) solution of pentamethylcy-
clopentadiene (14.1 mL, 90.0 mmol) in THF (200 mL), and the
resultant mixture was stirred at room temperature for 2 h.
The suspension C was transferred via cannula to the suspension
A, and the mixture was stirred at room temperature for 1 h; its
color turned to green. Then suspension B was added via cannula,
(15) Crystallographic data for the structures reported in this paper have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publications no. CCDC-293068 (K1) and CCDC-293069
(K2). Copies of the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax, (+44)1223-336-
033; e-mail, deposit@ccdc.cam.ac.uk).
(16) For systematic studies on crystal structures of [(η3-allyl)(PHOX)-
Pd] complexes, see: (a) Kollmar, M.; Goldfuss, B.; Reggelin, M.; Rominger,
F.; Helmchen, G. Chem.sEur. J. 2001, 7, 4913-4927. (b) Kollmar, M.;
Steinhagen, H.; Janssen, J. P.; Goldfuss, B.; Malinovskaya, S. A.; Va´zquez,
J.; Rominger, F.; Helmchen, G. Chem.sEur. J. 2002, 8, 3103-3114. (c)
Zehnder, M.; Schaffner, S.; Neuburger, M.; Plattner, D. A. Inorg. Chim.
Acta 2002, 337, 287-298 and references therein.
J. Org. Chem, Vol. 71, No. 6, 2006 2489

Geisler and Helmchen
FIGURE 3. Atom numbering for K1a.
FIGURE 6. X-ray Crystal Structure of K2 (hydrogen atoms and the
counteranion are omitted); color coding according to the Chem3D ultra
program; selected bond lengths (Å) with estimated standard deviations,
Pd-C1a, 2.128(3); Pd-C2a, 2.149(3); Pd-C3a, 2.262(3); selected angle
(ø), angle between the “best-fit” plane through the ligand atoms N,
C2, C6, C7, and P and the plane [N,Pd,P] ) 7.3°.
C17H22O2Fe (M+), 314.0969; found, 314.0984. Anal. Calcd for
C17H22O2Fe: C, 64.99; H, 7.06. Found: C, 65.20; H, 6.97.
General Procedure for the Preparation of the Amides 2a-
d. A solution of Me3Al (2.0 M in toluene, 2.28 equiv) was added
dropwise to a cold (0 °C) about 0.4 M solution of (S)-amino alcohol
(1.2 equiv) in toluene. The mixture was allowed to warm to room
temperature and was further stirred for 60 min. Then ester 1 was
added in one portion. The resulting orange mixture was heated at
reflux for 16 h (72 h in the case of 2b). After cooling to room
temperature, a 20% aqueous solution of Seignette’s salt was added
with care, and the resultant mixture was vigorously stirred for at
least 2 h. The organic layer was separated, and the aqueous layer
was extracted several times with EtOAc. The organic layers were
combined, washed with brine, dried (Na2SO4), and concentrated
in vacuo. The crude product was purified by column chromatog-
raphy (silica, petroleum ether/ethyl acetate, 2:1).
FIGURE 4. X-ray crystal structure of K1a (hydrogen atoms and the
counteranion are omitted); color coding according to the Chem3D ultra
program; selected bond lengths (Å) with estimated standard deviations,
Pd-C1a, 2.101(3); Pd-C2a, 2.181(3); Pd-C3a, 2.240(3); selected angle
(ø), angle between the “best-fit” plane through the ligand atoms N,
C2, C6, C7, and P and the plane [N,Pd,P] ) 23.4°.
(1S)-N-(1-Hydroxymethyl-2,2-dimethylprop-1-yl)-1′,2′,3′,4′,5′-
pentamethylferroceneamide (2b). Following the general proce-
dure, 1 (6.00 g, 19.1 mmol), (S)-tert-leucinol (2.69 g, 22.9
mmol), and Me3Al (21.0 mL of a 2.0 M solution in toluene,
42.0 mmol) were reacted in toluene (55 mL) to afford 6.74 g
(88%) of 2b as yellow solid. Mp 126-127 °C. TLC: Rf ) 0.17
(petroleum ether/ethyl acetate 2:1). [R]20 -56.2 (c 0.34, EtOH).
D
1H NMR (300.13 MHz, CD2Cl2): δ 5.68 (d, J ) 5.8 Hz, 1H,
CONH), 4.07 (br s, 1H, HFc), 4.04 (br s, 1H, HFc), 3.90 (br s,
2H, HFc), 3.85 (m, 1H, CH2OH), 3.77 (dt, J ) 7.5, 2.6 Hz, 1H,
NHCH), 3.59 (dd, J ) 10.6, 7.5 Hz, 1H, CH2OH), 3.55 (br s,
1H, OH), 1.82 (s, 15H, CFcsCH3), 1.00 (s, 9H, C(CH3)3). 13C
NMR (75.47 MHz, CDCl3): δ 171.4 (s, CONH), 81.3 (5s,
CFcsCH3), 77.5 (s, CFcsCONH), 74.7 (2d, CFcsH), 70.6 (2d,
CFcsH), 64.6 (t, CH2OH), 61.3 (d, NHCH), 33.3 (s, C(CH3)3), 27.0
(3q, C(CH3)3), 10.5 (5s, CFcsCH3). HRMS (FAB) m/z calcd for
C22H33NO2Fe (M+), 399.1861; found, 399.1805. Anal. Calcd for
C22H33NO2Fe: C, 66.17; H, 8.33; N, 3.51. Found: C, 65.92; H,
8.45; N, 3.74.
General Procedure for the Preparation of Oxazolines 3a-d.
A solution of amide 2 and NEt3 (5 equiv) in CH2Cl2 (6 equiv) was
stirred with molecular sieves (4 Å) at room temperature for 1 h.
Then TsCl (1.05 equiv) was added, and the reaction mixture was
stirred at room temperature for 2 d. It was then treated with saturated
aqueous NH4Cl and extracted with CH2Cl2. Drying over anhydrous
Na2SO4, filtration, and concentration in vacuo gave the crude
product, which was purified by column chromatography (silica,
petroleum ether/ethyl acetate, 9:1).
FIGURE 5. Atom numbering for K2.
and the resultant mixture was stirred at room temperature for 16 h.
The solvents were then removed in vacuo, the residue was dissolved
in ether/n-pentane 1:1, and the solution was filtered through a short
1
pad of alumina (neutral, 13% H2O). A H NMR spectrum of the
crude product showed a mixture of 1 (93%), dimethyl ferrocene-
dicarboxylate (5%), and ferrocenes (1,2,3,4,5-pentamethylferrocene
and decamethylferrocene, 2%). Column chromatography (silica,
petroleum ether/diethyl ether, 9:1) afforded 15.25 g (59%) of pure
1 as an orange solid. Mp 96-98 °C. TLC: Rf ) 0.34 (petroleum
1
ether/diethyl ether, 9:1). H NMR (300.13 MHz, CDCl3): δ 4.26
(t, J ) 1.8 Hz, 2H, HFc), 3.94 (t, J ) 1.8 Hz, 2H, HFc), 3.81 (s, 3H,
CO2CH3), 1.82 (s, 15H, CFcsCH3). 13C NMR (75.47 MHz,
CDCl3): δ 171.5 (s, CO2CH3), 81.8 (5s, CFcsCH3), 79.2 (s,
CFcsCO2CH3), 75.6 (2d, CFcsH), 72.9 (2d, CFcsH), 51.4 (q,
CO2CH3), 10.8 (5q, CFcsCH3). HRMS (FAB) m/z calcd for
2490 J. Org. Chem., Vol. 71, No. 6, 2006

Synthesis of Chiral Phosphinooxazoline Ligands
1-[4(S)-tert-Butyl-2-oxazolin-2-yl]-1′,2′,3′,4′,5′-pentamethylfer-
rocene (3b). Following the general procedure, 2b (0.876 g, 2.19
mmol) was reacted with TsCl (0.423 g, 2.21 mmol) in a mixture
of NEt3 (1.34 mL, 9.6 mmol) and CH2Cl2 (0.81 mL, 11.6 mmol)
to afford 0.758 g (91%) of 3b as an orange liquid. TLC: Rf )
vacuo. The residue was subjected to column chromatography (silica,
n-pentane/diethyl ether, 9:1).
BSA-Method: A solution of [Pd(η3-C3H5)Cl]2 (5 µmol) and the
ligand (11 µmol) in dry THF (1 mL) was stirred for 10 min at
room temperature. Substrate 4 (1.0 mmol) was added, and the
resultant orange-red mixture was stirred for 10 min at room
temperature. The reaction temperature was adjusted, and then
dimethyl malonate (3.0 mmol) and BSA (3.0 mmol) were added.
The reaction was started by the addition of sodium acetate (0.03
mmol), and the conversion was monitored by TLC (petroleum ether/
ethyl acetate, 4:1, detection of spots with iodine vapor). After the
disappearance of the substrate, saturated aqueous NH4Cl solution
(10 mL) was added, and the mixture was extracted with ethyl acetate
(5 ×). The organic layer was dried over Na2SO4 and concentrated
in vacuo. The residue was subjected to column chromatography
(silica, n-pentane/diethyl ether, 9:1).
0.47 (petroleum ether/ethyl acetate, 9:1). [R]20 49.6 (c 0.63,
D
1
CHCl3). H NMR (300.13 MHz, CDCl3): δ 4.28 (mc, 1H, HFc),
4.26 (dd, J ) 9.8, 8.4 Hz, 1H, OCH2), 4.15 (mc, 1H, HFc), 4.06
(t, J ) 8.4 Hz, 1H, OCH2), 3.92 (dd, J ) 9.8, 8.6 Hz, 1H,
CdNsCH), 3.85 (t, J ) 1.9 Hz, 2H, HFc), 1.84 (s, 15 H,
CFcsCH3), 0.94 (s, 9H, C(CH3)3). 13C NMR (75.47 MHz, CDCl3):
δ 165.1 (s, OCdN), 81.6 (5s, CFcsCH3), 77.6 (d, CdNsCH), 74.4
(d, CFcsH), 74.2 (d, CFcsH), 72.4 (s, CFcsCox), 71.8 (d, CFcsH),
71.6 (d, CFcsH), 68.3 (t, OCH2), 34.0 (s, C(CH3)3), 26.5 (3q,
C(CH3)3), 11.0 (5q, CFcsCH3). HRMS (EI) m/z calcd for
C22H31NOFe (M+), 381.1755; found, 381.1746. Anal. Calcd for
C22H31NOFe: C, 69.29; H, 8.19; N, 3.67. Found: C, 69.13; H,
8.25; N, 3.61.
General Procedure for the Preparation of L1-L5. A cold
(-78 °C) solution of 3 and TMEDA (1.3 equiv) in Et2O was treated
dropwise with precooled sec-butyllithium (1.3 M solution in
cyclohexane, 1.3 equiv). The resultant solution was stirred for 1 h,
treated with an electrophile (1.3 equiv), and then allowed to warm
to room temperature over a period of 2 h. The solvent was removed
in vacuo, the resulting slurry was treated with aqueous NaHCO3
solution, and the mixture was then extracted with CH2Cl2. The
combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo. The crude product was purified by column
chromatography (silica, CH2Cl2/MeOH, 99:1). In all cases, starting
material was recovered.
Complex K1. A mixture of [Pd(η3-C3H5)Cl]2 (18.3 mg, 50.0
µmol), L2 (56.6 mg, 100.0 µmol), and CH2Cl2 (2 mL, degassed)
was stirred for 10 min at room temperature to give a clear orange-
red solution. Then a solution of AgSbF6 (34.4 mg, 100.0 µmol) in
methanol (0.5 mL, degassed) was added, and the resultant dark-
red mixture was stirred for 1 h under exclusion of light. Filtration
through Celite and evaporation of the solvents yielded 92.9 mg
(97%) of K1 as a red solid. Crystals suitable for X-ray crystal
structure determination were grown by slow diffusion of Et2O into
a solution of K1 in CH2Cl2 at room temperature. Structure a
(77%): 1H NMR (500.13 MHz, CDCl3) δ 7.94-7.82 (m, 2H, HPh),
7.80-7.64 (m, 3H, HPh), 7.36-7.26 (m, 3H, HPh), 6.93-6.83 (m,
2H, HPh), 5.62 (mc, 1H, Hallyl), 4.91 (m, 1H, Hallyl), 4.76 (m, 1H,
HFc), 4.65 (m, 1H, OCH2), 4.57 (dd, J ) 9.2, 5.5 Hz, 1H, OCH2),
4.40 (m, 1H, HFc), 4.33 (m, 1H, HFc), 4.19 (m, 1H, CdNsCH),
3.84 (dd, J ) 14.1, 8.6 Hz, 1H, Hallyl), 3.14 (m, 1H, Hallyl), 1.46 (s,
15H, CFcsCH3), 1.41 (m, 1H, Hallyl), 1.13 (s, 9H, C(CH3)3); 13C
NMR (75.47 MHz, CDCl3) δ 174.9, 136.4 (JC,P ) 16.0 Hz), 133.2,
131.2 (JC,P ) 13.2 Hz), 130.2, 130.1 (JC,P ) 12.2 Hz), 128.8
(JC,P ) 12.2 Hz), 121.7, 87.2, 84.3, 81.1, 80.1, 79.2, 70.7, 55.3,
35.0, 27.3, 10.9, quartet of C’s missing; 31P NMR (121.49
MHz, CDCl3) δ 16.6. Structure b (23%): 1H NMR (500.13
MHz, CDCl3) δ 8.09-7.98 (m, 2H, HPh), 7.80-7.64 (m, 3H, HPh),
7.36-7.26 (m, 3H, HPh), 6.93-6.83 (m, 2H, HPh), 5.24 (mc, 1H),
4.81-4.68 (m, 2H), 4.65 (m, 1H), 4.57 (m, 1H), 4.40 (m, 1H),
4.33 (m, 1H), 4.11 (m, 1H), 3.51 (m, 1H), 2.84 (m, 1H), 2.33 (m,
1H), 1.46 (s, 15H, CFcsCH3), 1.18 (s, 9H, C(CH3)3); 13C NMR
(75.47 MHz, CDCl3) intensities too low for safe assignments; 31P
NMR (121.49 MHz, CDCl3) δ 14.7. HRMS (FAB) m/z calcd for
C37H45NOPFe110Pd121SbF6 (M+), 951.0582; found, 951.0594; m/z
calcd for C37H45NOPFe108Pd121SbF6 (M+), 949.0569; found, 949.0573;
m/z calcd for C37H45NOPFe106Pd121SbF6 (M+), 947.0565; found,
947.0557; m/z calcd for C37H45NOPFe105Pd121SbF6 (M+), 946.0582;
found, 946.0579.
1-[4(S)-tert-Butyl-2-oxazolin-2-yl]-2(pS)-(diphenylphosphino)-
1′,2′,3′,4′,5′-pentamethylferrocene (L2). Following the general
procedure, 3b (3.263 g, 8.56 mmol) was reacted with sec-
butyllithium (8.56 mL of a 1.3 M solution in cyclohexane, 11.13
mmol), TMEDA (1.65 mL, 11.13 mmol), and PPh2Cl (2.456 g,
11.13 mmol) in Et2O (8.5 mL) to afford (after workup) 1.842 g
(3.26 mmol, 38%) of L2 as a yellow solid. Mp 105-108 °C.
TLC: Rf ) 0.64 (CH2Cl2/MeOH, 98:2). [R]20D 185 (c 0.28, EtOH).
1H NMR (500.13 MHz, CDCl3): δ 7.57-7.51 (m, 2H, HPh), 7.35-
7.27 (m, 3H, HPh), 7.19-7.11 (m, 5H, HPh), 4.49 (br s, 1H, HFc),
4.16 (t, J ) 9.0 Hz, 1H, OCH2), 3.94 (t, J ) 2.4 Hz, 1H, HFc),
3.73 (t, J ) 9.2 Hz, 1H, CdNsCH), 3.55 (t, J ) 8.5 Hz, 1H,
OCH2), 3.27 (br s, 1H, HFc), 1.82 (s, 15H, CFcsCH3), 0.65 (s, 9H,
C(CH3)3). 13C NMR (125.76 MHz, CDCl3): δ 164.8 (s, OCdN),
1
1
140.7 (d, JC,P ) 14.1 Hz, CPhsP), 139.0 (d, JC,P ) 14.1 Hz,
CPhsP), 136.2 (d, CPh), 136.0 (d, CPh), 132.7 (d, CPh), 132.6 (d,
CPh), 129.3 (d, CPh), 128.4 (d, CPh), 128.3 (d, CPh), 128.3 (d, CPh),
128.2 (d, CPh), 127.9 (d, CPh), 81.9 (5s, CFcsCH3), 78.9 (d, 1JC,P
)
15.2 Hz, CFcsP), 76.8 (d, CFcsH), 76.2 (d, CdNsCH), 75.7 (d,
CFcsH), 75.5 (d, CFcsH), 68.4 (t, OCH2), 33.7 (s, C(CH3)3), 26.2
(3q, C(CH3)3), 11.1 (5q, CFcsCH3). 31P NMR (202.46 MHz,
CDCl3): δ -23.8. HRMS (FAB) m/z calcd for C34H40NOPFe (M+),
565.2197; found, 565.2204. Anal. Calcd for C34H40NOPFe: C,
72.21; H, 7.13; N, 2.48; P, 5.48. Found: C, 71.92; H, 7.11; N,
2.49; P, 5.61.
General Procedure for the Allylic Alkylation of Cyclic
Substrates 4. Dimethyl Sodiomalonate as a Nucleophile: A
solution of [Pd(η3-C3H5)Cl]2 (5 µmol) and the ligand (11 µmol) in
dry THF (1 mL) was stirred for 10 min at room temperature. Sub-
strate 4 (1.0 mmol) was added, and the resultant orange-red mixture
was stirred for 10 min at room temperature. The reaction temper-
ature was adjusted, and a clear solution of dimethyl sodiomalonate,
kept at the same temperature, was added. This was prepared from
dimethyl malonate (1.5 mmol) and sodium hydride (1.1 mmol) in
THF (4 mL). Conversion was monitored by TLC (petroleum ether/
ethyl acetate, 4:1, detection of spots with iodine vapor). After the
complete reaction, saturated aqueous NH4Cl solution (10 mL) was
added, and the mixture was extracted with ethyl acetate (5 × 20
mL). The organic layer wasdried over Na2SO4 and concentrated in
Complex K2. A mixture of [Pd(η3-C6H9)Cl]2 (19.7 mg, 44.2
µmol), L2 (50.1 mg, 88.6 µmol), and CH2Cl2 (2 mL, degassed)
was stirred for 10 min at room temperature to give a clear orange-
red solution. Then a solution of AgSbF6 (30.4 mg, 88.6 µmol) in
methanol (0.5 mL, degassed) was added, and the resultant dark
red mixture was stirred for 1 h under exclusion of light. Filtration
through Celite and evaporation of the solvents yielded 85.1 mg
(86.1 µmol, 97%) of K2 as a red solid. Crystals suitable for X-ray
crystal structure determination were grown by slow diffusion of
Et2O into a solution of K2 in CH2Cl2 at room temperature. 1H NMR
(500.13 MHz, CDCl3): δ 7.95-7.79 (m, 2H, HPh), 7.75-7.60 (m,
3H, HPh), 7.39-7.29 (m, 3H, HPh), 7.03-6.86 (m, 2H, HPh), 5.90
(mc, 1H, Hallyl), 5.61 (t, J ) 7.0 Hz, 1H, Hallyl), 4.74 (mc, 1H,
HFc), 4.61 (t, J ) 9.4 Hz, 1H, OCH2), 4.57 (m, 1H, OCH2), 4.39
(m, 2H, HFc), 4.22 (dd, J ) 9.7, 5.1 Hz, 1H, CdNsCH), 3.95 (m,
1H, Hallyl), 1.97 (m, 1H, CH2), 1.71 (m, 1H, CH2), 1.44 (s, 15H,
CFcsCH3), 1.16 (m, 1H, CH2), 1.14 (s, 9H, C(CH3)3), 0.91-0.75
(m, 2H, CH2), -0.34 (m, 1H, CH2). 13C NMR (75.47 MHz,
1
CDCl3): δ 171.6 (s, OCdN), 136.5 (2d, CPh), 135.1 (d, JC,P
)
J. Org. Chem, Vol. 71, No. 6, 2006 2491

Geisler and Helmchen
1
49.0 Hz, CPhsP), 133.0 (2d, CPh), 131.8 (2d, CPh), 131.5 (d, JC,P
Acknowledgment. We thank B. Beele, R. Haufe, and O.
Tverskoy for experimental assistance and T. Oeser for the X-ray
crystal structure determinations.
) 48.0 Hz, CPhsP), 130.0 (2d, CPh), 128.8 (2d, CPh), 111.1 (d,
allyl), 103.3 (d, Callyl), 84.2 (5s, CFcsCH3), 80.4 (2d, CFcsH
C
and CdNsCH), 80.0 (d, CFcsH), 78.9 (d, CFcsH), 74.3 (d,
2JC,P ) 23.5 Hz, CFcsCox), 72.8 (d, JC,P ) 37.7 Hz, CFcsP),
1
Supporting Information Available: Syntheses and compound
characterization of compounds 2a, 2c, 2d, 3a, 3c, 3d, and L1-L5.
1H NMR spectra of compounds 1a-d, 2a-d, 3a-d, 5a-c,
L1-L5, K1, and K2. Tables of crystal data and structure refine-
ment and the full list of bond lengths and angles from the X-ray
crystallographic study of K1 and K2. This material is available
free of charge via the Internet at http://pubs.acs.org.
70.5 (t, OCH2), 68.5 (d, Callyl), 35.2 (s, C(CH3)3), 28.7 (t, CH2),
27.2 (3q, C(CH3)3), 25.1 (t, CH2), 20.6 (t, CH2), 10.9 (5q,
CFcsCH3). 31P NMR (121.49 MHz, CDCl3): δ 18.2 (s, inten-
sity 99%), 14.3 (s, intensity 1%). HRMS (FAB) m/z calcd for
C40H49NOPFe110Pd121SbF6 (M+), 991.0895; found, 991.0909; m/z
calcd for C40H49NOPFe108Pd121SbF6 (M+), 989.0883; found, 989.0899;
m/z calcd for C40H49NOPFe104Pd123SbF6 (M+), 987.0888; found,
987.0899; m/z calcd for C40H49NOPFe105Pd121SbF6 (M+), 986.0894;
found, 986.0919.
JO0526136
2492 J. Org. Chem., Vol. 71, No. 6, 2006