Oxazaphospholidine-oxide as an efficient ortho-directing group for the diastereoselective deprotonation of ferrocene

Article abstract of DOI:10.1021/ol0523704

Ortho-lithiation of (2R,4S,5R)-3,4-dimethyl-2-ferrocenyl-5-phenyl[1,3,2] oxazaphospholidine 2-oxide 2 was carried out with diastereoselectivity of >99%, affording a new and efficient way for introducing planar chirality into the ferrocene backbone. Various electrophiles were used to quench the lithiated species, showing the wide applicability of the new ortho-directing group and its potential to generate ligands for use in asymmetric catalysis.

Full text of DOI:10.1021/ol0523704

ORGANIC
LETTERS
2006
Vol. 8, No. 2
215-218
Oxazaphospholidine-oxide as an
Efficient ortho-Directing Group for the
Diastereoselective Deprotonation of
Ferrocene
Daniele Vinci,† Nuno Mateus,† Xiaofeng Wu,† Fred Hancock,‡
Alexander Steiner,† and Jianliang Xiao*,†
Department of Chemistry, UniVersity of LiVerpool, LiVerpool L69 7ZD, U.K.
j.xiao@liV.ac.uk
Received September 30, 2005
ABSTRACT
Ortho-lithiation of (2R,4S,5R)-3,4-dimethyl-2-ferrocenyl-5-phenyl[1,3,2]oxazaphospholidine 2-oxide 2 was carried out with diastereoselectivity
of >99%, affording a new and efficient way for introducing planar chirality into the ferrocene backbone. Various electrophiles were used to
quench the lithiated species, showing the wide applicability of the new ortho-directing group and its potential to generate ligands for use in
asymmetric catalysis.
The development of asymmetric catalysis in recent years has
resulted in an increasing demand for highly active and
selective ligands.1 In this context, planar chiral ferrocenes
have emerged as a dominant class of compounds for many
new catalytic processes.2,3
Since the pioneering work of Ugi et al.,4 the synthesis of
planar chiral ferrocenes has become of continuous interest.
Enantiopure 1,2-disubstituted ferrocenes can be accessed by
a variety of stereoselective ortho-metalation reactions. A
number of chiral ortho-directing groups have been developed
and studied; these include sulfoxides,5 acetals,6 oxazolines,7
hydrazones,8 azepines,9 sulfoximines,10 pyrrolidine,11 and
O-methyl ephedrine derivatives12 (Figure 1). Ortho-metala-
(5) (a) Rebie`re, F.; Riant, O.; Richard, L.; Kagan, H. B. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 568. (b) Riant, O.; Argouarch, G.; Guillaneux, D.;
Samuel, O.; Kagan, H. B. J. Org. Chem. 1998, 63, 3511.
(6) (a) Riant, O.; Samuel, O.; Kagan, H. B. J. Am. Chem. Soc. 1993,
115, 5835. (b) Riant, O.; Samuel, O.; Flessner, T.; Taudien, S.; Kagan, H.
B. J. Org. Chem. 1997, 62, 6733.
(7) (a) Richards, C. J.; Damalidis, T.; Hibbs, D. E.; Hursthouse, M. B.
Synlett 1995, 74. (b) Nishibayashi Y.; Uemura S. Synlett 1995, 79.
(8) (a) Enders, D.; Peters, R.; Lochtman, R.; Raabe, G. Angew. Chem.,
Int. Ed. 1999, 38, 2421. (b) Enders, D.; Peters, R.; Lochtman, R.; Runsink,
J. Eur. J. Org. Chem. 2000, 2839.
(9) Wildhalm, M.; Mereiter, K.; Bourghida, M. Tetrahedron: Asymmetry
1998, 9, 2983.
(10) Bolm, C.; Kesselgruber, M.; Muniz, K.; Raabe, G. Organometallics
2000, 19, 1648.
(11) Ganter, C.; Wagner, T. Chem. Ber. 1995, 128, 1157.
(12) (a) Kitzler, R.; Xiao, L.; Weissensteiner, W. Tetrahedron: Asym-
metry 2000, 11, 3459. (b) Xiao, L.; Kitzler, R.; Weissensteiner, W. J. Org.
Chem. 2001, 66, 8912.
† University of Liverpool.
‡ Johnson Matthey PCT, 28 Cambridge Science Park, Milton Road,
Cambridge, U.K. CB4 0FP.
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley:
New York, 1994. (b) Catalytic Asymmetric Synthesis; Ojima, I., Ed.;
VCH: Weinheim, 2000.
(2) (a) Ferrocenes; Togni, A., Hayashi, T., Eds.; VCH: Weinheim, 1995.
(b) Togni A. Angew. Chem., Int. Ed. Engl. 1996, 35, 1475. (c) Richards,
C. J.; Locke, A. J. Tetrahedron: Asymmetry 1998, 9, 2337.
(3) Reviews: (a) Atkinson, R. C. J.; Gibson, V. C.; Long, N. J. Chem.
Soc. ReV. 2004, 33, 313. (b) Oliver, B.; Sutcliffe, O. B.; Bryce, M. R.
Tetrahedron: Asymmetry 2003, 14, 2297. (c) Colacot T. J. Chem. ReV.
2003, 103, 3101.
(4) Markarding, D.; Klusacek, H.; Gokel, G.; Hoffmann, P.; Ugi, I. J.
Am. Chem. Soc. 1970, 92, 5389.
10.1021/ol0523704 CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/18/2005

Scheme 1
Figure 1. Ferrocene carrying ortho-directing groups.
tion directed by stereogenic phosphine oxides was also
reported for the synthesis of ferrocenyl diphosphines;13
however, the metalation process was nondiastereoselective
with organolithium reagents. Application of external chiral
auxiliaries, e.g., (-)-sparteine,14 (1R,2R)-N,N,N,′N′-tetra-
methylcyclohexane diamine,15 or chiral lithium amide16 bases
in combination with achiral ortho-directing groups, has also
been explored. However, most of these methodologies require
laborious resolutions of the starting material or the use of
expensive chiral reagents. Here we report an efficient, easily
accessible chiral ortho-directing group, the oxazaphospho-
lidine oxide, for the synthesis of diastereomerically pure 1,2-
disubstitued ferrocenes.
The starting compound 2 is prepared in two steps from
inexpensive (-)-ephedrine, with no resolution required.17 The
first step is the nucleophilic attack of (-)-ephedrine on PCl3.
Performing the reaction in toluene at -78 °C in the presence
of N-methyl morpholine leads to practically pure (2R,4S,5R)-
2-chloro-3,4-dimethyl-5-phenyl-l,3,2-oxazaphospholidine 1
in 75% yield. The second step is the quenching of mono-
lithiated ferrocene with previously prepared 1. Here the
monolithiation step is best performed according to slight
modification of the procedure reported by Mueller-Wester-
hoff.18 t-BuLi (1.1 equiv) is added to a solution of ferrocene
and t-BuOK in THF at -78 °C. After 1 h of stirring at room
temperature a fine red-brick precipitate is formed. The slurry
is transferred via cannula to a solution of 1 (1.5 equiv)
previously cooled to -78 °C, and the reaction is allowed to
reach room temperature. After overnight stirring, the mixture
is cooled to 0 °C and t-BuOOH (1.5 equiv) is added.
Aqueous workup and purification by SiO2 flash chromatog-
raphy gives 2 in 60% yield and over 99% de (Scheme 1).
The JPH value of 6.5 Hz for the coupling between P and
the 5-H proton on the ephedrine ring supports the configu-
ration shown for 2.19
Assuming that the oxidation step occurs with retention of
configuration,20 the substitution product is then formed with
retention of configuration as well. Further support for this
is found in the analogous reaction with BH3‚S(CH3)2, the
product of which was crystallized and analyzed by X-ray
diffraction. The resolved structure of 2a shows that the
substitution occurred with retention of configuration (Figure
2). The BH3 group points toward the other Cp ring, the
3
Figure 2. X-ray structure of 2a. Selected bond lengths (Å) and
angles (deg): P1-B1 1.877(5), P1-N1 1.681(3), P1-O1 1.604-
(2), P1-C10 1.792(4); O1-P1-N1 94.69(14), O1-P1-B1 117.3-
(2), N1-P1-B1 115.1(2).
(13) Nettekoven, U.; Widhalm, M.; Kamer, P. C. J.; Van Leeuwen, P.
W. N. M.; Mereiter, K.; Lutz, M.; Spek, A. Organometallics 2000, 19,
2299.
(14) (a) Tsukasaki, M.; Tinkl, M.; Roglans, A.; Chapell, B. J.; Taylor,
N. J.; Snieckus, V. J. Am. Chem. Soc. 1996, 118, 685. (b) Laufer, R. S.;
Veith, U.; Taylor, N. J.; Snieckus, V. Org. Lett. 2000, 2, 629. (c) Metallinos,
C.; Snieckus, V. Org. Lett. 2002, 4, 1935. (d) Metallinos, C.; Szillat, H.;
Taylor, N. J.; Snieckus, V. AdV. Synth. Catal. 2003, 345, 370.
(15) Nishibayashi, Y.; Arikawa, Y.; Ohe, K.; Uemura, S. J. Org. Chem.
1996, 61, 1172.
(16) Price, D.; Simpkins, N. S. Tetrahedron Lett. 1995, 36, 6135.
(17) (a) Cooper, D. B.; Hall, C. R.; Harrison, J. M.; Inch, T. D. J. Chem.
Soc., Perkin Trans. 1 1977, 1969. (b) Hall, C. R.; Inch, T. D. J. Chem.
Soc., Perkin Trans. 1 1979, 1104. (c) Carey, J. V.; Barker, M. D.; Brown,
J. M.; Russell, M. J. H. J. Chem. Soc. Perkin Trans. 1 1993, 831. (d) Iyer,
R. P.; Yu, D.; Ho, N. H.; Tan, W.; Agrawal, S. Tetrahedron: Asymmetry
1995, 6, 1051.
dihedral angle between the planes C9-C10-P1 and C10-
P1-B1 being 11.5(1)°. The ephedrine ring adopts a half-
chair conformation with its backbone pointing away from
the ferrocene moiety.
The overall retention of configuration could be rationalized
by a reaction sequence involving attack of FcLi on the
electrophilic phosphorus followed by pseudorotation and
termination by chloride elimination (eq 1, Scheme 2).21,22
(19) Schwalbe, C. H.; Chopra, G.; Freeman, S.; Brown, J. M.; Carey, J.
V. J. Chem. Soc., Perkin Trans. 2 1991, 2081.
(20) Denney, D. B.; Hanifin, W. J., Jr. Tetrahedron Lett. 1963, 30, 2177.
(21) Nielsen, J.; Dahl, O. J. Chem. Soc., Perkin Trans. 2 1984, 553.
(22) Sum, V.; Baird, C. A.; Kee, T. P.; Thornton-Pett, M. J. Chem. Soc.,
Perkin Trans. 1 1994, 3183.
(18) Sanders, R.; Mueller Westerhoff, U. T. J. Organomet. Chem. 1996,
512, 219.
216
Org. Lett., Vol. 8, No. 2, 2006

in Et2O at this temperature; only starting material was
recovered from these reaction mixtures.
Scheme 2
Using n-BuLi in THF, however, afforded 37% of the
desired product 4 in 99% de and about 50% of a side product
1
(Table 1). A careful examination of the H and 31P NMR
Table 1. Diastereoselective ortho-Lithiation of 2 under Various
Screening Conditionsa
Another less likely scenario could be the formation of a
phosphenium ion intermediate from the dissociation of Cl-
in the presence of the Lewis acidic lithium (eq 2, Scheme
2). This intermediate could be particularly stabilized by the
presence of a nitrogen atom, which would help to disperse
the positive charge by resonance.23 In such species, the
nitrogen, oxygen, and phosphorus atoms and the phosphorus
lone pairs would be in the same plane. The bottom face of
the intermediate would be more hindered as a result of the
configurations of the methyl and phenyl groups lying below
the five-membered ring of the ephedrine skeleton. The
nucleophile would then attack the phosphorus from the top,
generating the substituted product with retention of config-
uration.
We also observed that using a lower concentration of 1
(1 equiv to the ferrocene), a mixture containing approxi-
mately 43% of 2 and 28% of a bissubstituted compound 3
was formed, as evidenced by the 31P NMR of the crude
product. Under these conditions the nucleophilic attack of
the ferrocenyllithium at 1 competes with the attack at the
newly formed 2b (Scheme 3). With a lower amount of 1,
entry
solvent
RLi
isolated yield (%)
deb (%)
1
2
3
4c
THF
THF
THF
THF
n-BuLi
s-BuLi
t-BuLi
t-BuLi
37
66
95
77
>99
>99
>99
>99
a Reaction condition: 1 equiv of 2, 1.5 equiv of RLi, 1.5 equiv of CH3I,
-78 °C. b Determined by 31P NMR; a value of >99% was assigned when
the other diastereomer was not detected. c 2 equiv of RLi.
spectroscopic data revealed that some of the n-BuLi had
attacked the phospholidine ring to cleave the P-O bond to
give a Li-alkoxide species that had reacted with MeI to give
4a (Scheme 4). This suggested that a more basic and less
Scheme 4
Scheme 3
nucleophilic organolithium reagent was necessary. Accord-
ingly, s-BuLi was able to afford 66% of 4, and t-BuLi
allowed an even more efficient deprotonation process on the
Cp ring, affording the methyl derivative 4 with 95% isolated
yield and over 99% de. Using 2 equiv of t-BuLi did not give
better results because of competing deprotonation at the
benzylic position (Table 1). The absolute configuration of 4
was determined from X-ray analysis (Figure 3).
The resolved structure shows that 4 is planar chiral with
configuration R. The O2 atom lies cis to the C16 methyl
and points down to the bottom Cp ring. The dihedral angle
between the plane O2-P1-C11 and C15-C11-P1 amounts
to 22.0(4)°. The corresponding torsion angle in the other
crystallographically independent molecule is similar, at 13.1-
(4)°. This suggests possible assistance by O2 in the depro-
tonation at C15 by t-BuLi and stabilization of the resulting
lithiated species by O2 coordination to lithium.
the reaction with ferrocenyllithium was also slowed in accord
with a mechanism where the rate of the reaction was
dependent on the concentration of the electrophile.
Solvents, source of lithium, and substrate/lithium ratios
have been shown to play an important role in the diaster-
eselective deprotonation of ferrocene.6-16 To examine if the
oxazaphosphilidine oxide moiety could be used as an ortho-
directing group, we first studied these parameters in the
lithiation followed by reaction with an electrophile, MeI. All
reactions were performed at -78 °C to prevent deprotonation
at the benzylic position on the phospholidine ring. It appeared
quite clear from the beginning that THF was the best solvent.
In fact, 2 was not soluble in hexane and only slightly soluble
Using the conditions established, a variety of electrophiles
were next examined in this reaction. A summary of the
results obtained is reported in Table 2.
(23) (a) Fleming, S.; Lupton, M. K.; Jekot, K. Inorg. Chem. 1972, 11,
2534. (b) Maryanoff, B. E.; Hutchins, R. O. J. Org. Chem. 1972, 37, 3475.
Org. Lett., Vol. 8, No. 2, 2006
217

silanes, alcohols, and phosphines. All reactions proceeded
to completion, with all products being isolated as solids after
SiO2 flash chromatography purification. Assuming that the
lithiation process is independent of the electrophile chosen,
we assigned the absolute configuration based on the results
obtained for 4.
In conclusion, we have established a simple and convenient
methodology for the synthesis of diastereomerically pure,
functionalized ferrocenyl compounds. We found the oxaza-
phospholidine oxide moiety to be a new and excellent ortho-
directing group for the stereoselective deprotonation of
ferrocene. With this methodology, we produced a range of
1,2-disubstituted ferrocene derivatives possessing planar
chirality, including electronically and sterically diverse
phosphines (Figure 4). Possible applications of the ligands
Figure 3. X-ray structure of (Rp)-4. Only one of the two
crystallographically independent molecules is shown. Selected bond
lengths (Å) and angles (deg): N1-P1 1.669(3), O1-P1 1.600(3),
O2-P1 1.467(2), P1-C11 1.765(3); O2-P1-O1 116.40(14), O2-
P1-N1 115.27(15), O1-P1-N1 95.03(14).
Our methodology was shown to be compatible with a
number of functionalities: alkyls, halogens, boronates,
Table 2. Diastereoselective ortho-Lithiation of 2a
entry
E(X)
Me(I)
I(I)
TMS(Cl)
TES(Cl)
yield (%)
deb (%)
main product
1
2
3
4
5
6
7
8
9
95
76
94
70
61
73
65
68
72
45
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
(Rp)-4
(Sp)-5
(Rp)-6
(Rp)-7
(Rp)-8c
(Rp)-9d
(Rp)-10
(Rp)-11
(Rp)-12
(Rp)-13
Figure 4. Planar chiral ferrocenyl phosphines.
in asymmetric catalysis are being pursued in our laboratory.
Ph2CO
B(OMe)3
PPh2(Cl)
PCy2(Cl)
P(pTFP)2(Cl)e
P(pMOP)2(Cl)e
Acknowledgment. We are grateful to Jamie Bickley for
collection of X-ray data and Johnson Matthey for financial
support (D.V.).
10
Supporting Information Available: Experimental pro-
cedures and analytical data, including CIF files. This material
is available free of charge via the Internet at http://pubs.acs.org.
a Reaction condition: 1 equiv of 2, 1.5 equiv of RLi, 1.5 equiv of EX,
-78 °C. b Determined by 31P NMR; see Table 1. c E ) Ph2COH. d E )
B(OH)2. e See Figure 4 for structures.
OL0523704
218
Org. Lett., Vol. 8, No. 2, 2006