O-Methylephedrine: A versatile and highly efficient ortho-directing group. Synthesis of enantiopure 1,2-disubstituted ferrocene derivatives

Article abstract of DOI:10.1021/jo015949y

O-Methylephedrine was identified as a very efficient chiral auxiliary for ortho-lithiation reactions of ferrocenes. (1R,2S)-O-Methylephedrine [CH₃NHCH(CH₃)CH(Ph)OCH₃] was reacted with N-ferrocenylmethyl-N,N,N-trimethylammo

Full text of DOI:10.1021/jo015949y

8
912
J . Org. Chem. 2001, 66, 8912-8919
O-Meth ylep h ed r in e: A Ver sa tile a n d High ly Efficien t
or th o-Dir ectin g Gr ou p . Syn th esis of En a n tiop u r e 1,2-Disu bstitu ted
F er r ocen e Der iva tives
Li Xiao, Roman Kitzler, and Walter Weissensteiner*
Institute of Organic Chemistry, University of Vienna, A-1090 Wien, Austria
walter.weissensteiner@univie.ac.at
Received J uly 19, 2001
O-Methylephedrine was identified as a very efficient chiral auxiliary for ortho-lithiation reactions
of ferrocenes. (1R,2S)-O-Methylephedrine [CH
ferrocenylmethyl-N,N,N-trimethylammonium iodide [FcCH
1R,2S)-N-ferrocenylmethyl-O-methylephedrine. Treatment of this compound with t-BuLi in pentane
followed by quenching with the electrophiles iodine, dibromotetrafluoroethane, chlorodiphenylphos-
phine or benzophenone gave 2-substituted ferrocenes in 98% de and with the (R )-ferrocene
3
NHCH(CH
3
)CH(Ph)OCH
3
] was reacted with N-
2
N(CH I; Fc ) ferrocenyl] to give
3 3
)
(
p
configuration. Subsequently, the chiral auxiliary could be replaced by systems including dimethyl-
amine, acetate, diaryl- or dialkylphosphines to give a number of enantiopure bifunctional
1
,2-disubstituted ferrocene derivatives such as (R
yldimethylamine or (R )-2-acetoxymethyl-1-diphenylphosphinoferrocene. As an application, ferro-
cenyl diphosphines possessing a planar (R )-ferrocene configuration only {1,2-(PPh )FcCH PR , R
Cy, Ph, [3,5-(CF Ph]} were synthesized in three steps from O-methylephedrine and N-
ferrocenylmethyl-N,N,N-trimethylammonium iodide in up to 77% overall yield.
p p
)-N-2-iodo- or (R )-N-2-bromoferrocenylmeth-
p
p
2
2
2
)
3 2
)
In tr od u ction
Enantiopure 1,2-disubstituted ferrocene derivatives are
Sch em e 1
widely used as ligands in homogeneous transition metal
1
catalysts. Typical examples are the aminophosphine
ppfa,2 the diphosphine J osiphos and the industrially
3
4
important Xyliphos (Scheme 1). On the basis of common
synthetic protocols, e.g., ortho-lithiation with n- or sec-
2
BuLi and quenching with an electrophile followed by
nucleophilic displacement of the dimethylamino group,2
hundreds of bi- and multifunctional catalyst ligands have
been prepared from commercially available (S)- or (R)-
,3
1
-(N,N-dimethylamino)ethylferrocene5 (Ugi’s amine,
Scheme 1).
Common characteristics of these ligands include the
ferrocenylethyl backbone and the presence of both central
and planar chirality. Although these systems have been
2
known for quite some time, until recently comparably
little attention has been paid to ligands based on a ferro-
cenylmethyl backbone or, more generally, to ferrocene
ligands possessing planar chirality only. Reported ex-
(
1) (a) Ferrocenes, Homogeneous Catalysis, Organic Synthesis, Mate-
rial Science; Togni, A., Hayashi, T., Eds.; VCH: Weinheim, 1995. (b)
Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH: New York
000.
2) (a) Hayashi, T.; Mise, T.; Fukushima, M.; Kagotani, M.; Na-
gashima, N.; Hamada, Y.; Matsumoto, A.; Kawakami, S.; Konishi, M.;
2,6
7
amples include ppfa and J osiphos analogues (Scheme
).
In general, the synthesis of enantiopure or enantio-
1
2
(
merically enriched 1,2-disubstituted ferrocenes involves
either a traditional resolution2 of racemic intermediates
or a stereoselective ortho-metalation step. However, while
the course of the metalation of Ugi’s amine is directed
by the configuration of the stereogenic center, the related
ferrocenylmethyl derivatives require a chiral auxiliary
to achieve stereoselectivity. The stereoselective ortho-
metalations reported to date include cyclopalladation of
Yamamoto, K.; Kumada, M. Bull. Chem. Soc. J pn. 1980, 53, 1138.
,6
(
3) Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Landert, H.;
Tijani, A. J . Am. Chem. Soc. 1994, 116, 4062.
4) (a) J alett, H.-P.; Spindler, F.; Blaser, H.-U.; Hanreich, R. G.
Ciba-Geigy A.-G., Switzerland) PCT Int. Appl. WO 9521151 A1
9950810, 1995. (b) J alett, H.-P.; Spindler, F.; Hanreich, R. G. (Ciba-
Geigy A.-G., Switzerland) PCT Int. Appl. WO 9641793 A1 19961227,
996 (c) J alett, H.-P.; Siebenhaar, B. (Ciba-Geigy A.-G., Switzerland)
(
(
1
1
PCT Int. Appl. WO 9705095 A1 19970213, 1996. (d) Sablong, R.;
Osborn, J . A.; Spindler, F. (Ciba-Geigy A.-G., Switzerland) PCT Int.
Appl. WO 9705094 A1 19970213, 1996. (e) Bieler, N.; Egli, P.; Dorta,
R.; Togni, A.; Eyer, M. (Lonza A. G., Switzerland) Eur. Pat. Appl. EP
9
09762 A2 19990421, 1998.
5) (a) Marquarding, D.; Klusacek, H.; Gokel, G.; Hoffmann, P.; Ugi,
(6) Xiao, L.; Mereiter, K.; Weissensteiner, W.; Widhalm, M. Syn-
thesis 1999, 8, 1354.
(
I. J . Am. Chem. Soc. 1970, 92, 5389. (b) Gokel, G., Ugi, I. J . Chem.
Educ. 1972, 49, 294.
(7) Argouarch, G.; Samuel, O.; Kagan, H. B. Eur. J . Org. Chem.
2000, 16, 2885.
1
0.1021/jo015949y CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/29/2001

Enantiopure 1,2-Disubstituted Ferrocene Derivatives
J . Org. Chem., Vol. 66, No. 26, 2001 8913
Sch em e 2
(
dimethylaminomethyl)ferrocene,8 ortho-metalation of
yield, respectively). Hydrogenation of both diastereomers
of 1 in EtOH/H O with RuO as the catalyst cleanly gave
9
10
11
ferrocenyl sulfoxides or dioxanes, amines, amides,
2
2
1
2
13
phosphineoxides, ferrocenyl oxazolines, ferrocenyl-
the cyclohexyl derivatives (1R,2S)-2 (74%) and (1S,2S)-2
(80%) with full retention of configuration (Scheme 2).
Each diastereomer of 1 and 2 was considered to be a
potential ortho-directing chiral auxiliary and was reacted
with N-ferrocenylmethyl-N,N,N-trimethylammonium io-
dide ([FcCH N(CH ) ]I) to give ferrocene derivatives
hydrazones,14 azepines, methoxy- or methoxymethyl-
15
16
pyrrolidine derivatives.6
,17
Recently, we reported briefly on O-methylephedrine as
a readily available and highly efficient new ortho-
directing group.18 Herein, we describe the potential of
O-methylephedrine and three related O-methylated amino
alcohols in the synthesis of enantiopure 1,2-disubstituted
planar chiral ferrocene derivatives. Several synthetic
protocols are given for the synthesis of diphosphines that
possess only planar chirality.
2
3 3
(1R,2S)-3 and (1S,2S)-3 as well as (1R,2S)-4 and (1S,2S)-
4. All four ferrocenyl intermediates were subjected to
ortho-lithiation reactions under different reaction condi-
tions. The lithiation reagent, solvent, and the general
reaction conditions were varied. Iodine, which is a very
reactive electrophile, was found to work best for screening
purposes. In a typical reaction (1R,2S)-3 was reacted in
diethyl ether at -78 °C with sec-BuLi. The reaction
mixture was stirred for 1.5 h at -78 °C and 1.5 h at -30
Resu lts a n d Discu ssion
(1R,2S)-O-Methylephedrine [(1R,2S)-N-methyl-1-meth-
oxy-1-phenylprop-2-ylamine, (1R,2S)-1] and its diastereo-
mer (1S,2S)-O-methyl-pseudo-ephedrine [(1S,2S)-N-meth-
°
C, and the resulting suspension was reacted at -78 °C
with a solution of iodine in THF. This procedure gave
rise to products (1R,2S,R )-5 and (1R,2S,S )-5 in a ratio
of 1:9 [only the products with the (R )-configuration are
yl-1-methoxy-1-phenylprop-2-ylamine, (1S,2S)-1] are easily
p
p
accessible by O-methylation1
9,20
of (1R,2S)-ephedrine or
3
1S,2S)-pseudo-ephedrine (KH, CH I, THF, 86% and 64%
p
(
represented in Scheme 2]. Table 1 summarizes selected
ortho-lithiation results obtained in the reaction of each
diastereomer of 3 and 4 with iodine as the electrophile
to give products 5 and 6.
The results listed in Table 1 show that the outcome of
the reaction depends strongly on the lithiation agent,
solvent and chiral auxiliary. In general, acceptable to
very high conversions were obtained with sec-BuLi and
t-BuLi in diethyl ether or pentane but the use of n-BuLi
as the lithiating agent or THF as the solvent (entries 1
and 6) led to a lithiation reaction that was very slow or
did not occur at all. The best result was obtained with
(1R,2S)-3 and t-BuLi in pentane, which gave product 5
(
8) Sokolov, V. I.; Troitskaya, L. L.; Gautheron B.; Tainturier, G. J .
Organomet. Chem. 1982, 235, 369.
9) (a) Riant, O.; Samuel O.; Kagan, H. B. J . Am. Chem. Soc. 1993,
15, 5835. (b) Riant, O.; Samuel, O.; Flessner, T.; Taudien S.; Kagan,
(
1
H. B. J . Org. Chem. 1997, 62, 6733. (c) Riant, O.; Argouarch, G.;
Guillaneux, D.; Samuel, O.; Kagan, H. B. J . Org. Chem. 1998, 63, 3511.
10) Nishibayashi, Y.; Arikawa, Y.; Ohe K.; Uemura, S. J . Org.
Chem. 1996, 61, 1172.
11) (a) Tsukazaki, M.; Tinkl, M.; Roglans, A.; Chapell, B. J .; Taylor
N. J .; Snieckus, V. J . Am. Chem. Soc. 1996, 118, 685. (b) J endralla,
H.; Paulus, E. Synlett 1997, 471. (c) Laufer, R. S.; Veith, U.; Taylor,
N. J .; Snieckus, V. Org. Lett. 2000, 2, 629.
(
(
(
(
12) Price D.; Simpkins, N. S. Tetrahedron Lett. 1995, 36, 6135.
13) (a) Richards, J .; Damalidis, T.; Hibbs D. E.; Hursthouse, M. B.
Synlett 1995, 74. (b) Sammakai, T.; Latham H. A.; Schaad, D. R. J .
Org. Chem. 1995, 60, 10. (c) Nishibayashi Y.; Uemura, S. Synlett 1995,
in 98% de and with the (R
p
)-ferrocene configuration
7
9. (d) Sammakai T.; Latham, H. A. J . Org. Chem. 1995, 60, 6002. (e)
Zhang, W.; Adachi, Y.; Hirao, T.; Ikeda, I. Tetrahedron: Asymmetry
996, 7, 451. Nishibayashi, Y.; Segawa, K.; Arikawa, Y.; Ohe, K.; Hidai,
M.; Uemura, S. J . Organomet. Chem. 1997, 545-546, 381.
14) (a) Enders, D.; Peters, R.; Lochtman, R.; Runsink, J . Synlett
997, 1462. (b) Enders, D.; Peters, R.; Lochtman, R.; Raabe, G.;
Runsink, J .; Bats, J . W. Eur. J . Org. Chem. 2000, 20, 3399.
15) (a) Widhalm, M.; Mereiter K.; Bourghida, M. Tetrahedron:
(entry 7). Changing the solvent to diethyl ether reduced
1
the diastereoselectivity to 86% but did not alter the
ferrocene configuration (entry 4). The reaction of the
same substrate, (1R,2S)-3, with sec-BuLi is heavily
dependent on the solvent used. The use of pentane gives
(
1
(
Asymmetry 1998, 9, 2983. (b) Widhalm, M.; Nettekoven, U.; Mereiter,
K. Tetrahedron: Asymmetry 1999, 10, 4369.
(19) (a) Tamao, K.; Kanatani, R.; Kumada, M. Tetrahedron Lett.
1984, 25, 1913. (b) N a¨ slund, J .; Welch, C. Tetrahedron: Asymmetry
1991, 2, 1123. (c) Chang, C. J .; Fang, J . M.; Liao, L. F. J . Org. Chem.
1993, 58, 1754.
(20) Tlahuext, H., Santiesteban, F., Garcia-Baez, E., Contreras, R.
Tetrahedron: Asymmetry 1994, 5, 1579.
(
16) Lotz, M.; Ireland, T.; Tappe, K.; Knochel, P. Chirality 2000,
1
2, 389.
(
(
17) Ganter C.; Wagner, T. Chem. Ber. 1995, 128, 1157.
18) Kitzler, R.; Xiao, L.; Weissensteiner, W. Tetrahedron: Asym-
metry 2000, 11, 3459.

8
914 J . Org. Chem., Vol. 66, No. 26, 2001
Xiao et al.
Ta ble 1. or th o-Lith ia tion of F er r ocen e Der iva tives 3 a n d
Sch em e 4
a
4
isolated
b
lithiation
agent
yield
(%)
de
main
entry substrate
solvent
ether
(%)
product
1
2
3
4
5
6
7
8
9
1
1
1
1
(1R,2S)-3 n-BuLi
0
(1R,2S)-3 sec-BuLi ether
(1R,2S)-3 sec-BuLi pentane 79
66
80
(1R,2S,S
(1R,2S,R
(1R,2S,R
p
)-5
79
86
85
p
p
p
)-5
)-5
)-5
(1R,2S)-3 t-BuLi
(1R,2S)-3 t-BuLi
(1R,2S)-3 t-BuLi
(1R,2S)-3 t-BuLi
(1S,2S)-3 sec-BuLi ether
(1S,2S)-3 t-BuLi
ether
ether
THF
65
65
<10
c
(1R,2S,R
d
d
n.d. n.d.
Sch em e 5
pentane 91
63
pentane 84
(1R,2S)-4 sec-BuLi ether 27
(1R,2S)-4 t-BuLi pentane 86
(1S,2S)-4 sec-BuLi ether 67
(1S,2S)-4 t-BuLi pentane 70
98
64
49
17
78
16
40
(1R,2S,R
p
)-5
(1S,2S,S
(1S,2S,R
(1R,2S,R
(1R,2S,S
(1S,2S,S
(1S,2S,R
p
)-5
)-5
)-6
p
0
1
2
3
p
p
)-6
)-6
p
p
)-6
a
General reaction conditions (except for entry 5): addition of
BuLi at -78 °C, 1.5 h at -78 °C; 2.5 (pentane) or 1.5 (ether, THF)
b
h at -30 °C; addition of iodine in THF at -78 °C. Of the mixture
of diastereomers; for isolated yields of the main product see
c
Experimental Section. Addition of BuLi at -78 °C, 3 h at -40
d
°
C; addition of iodine in THF at -78 °C. Because of low
conversion these values were not determined.
Sch em e 3
halides. These metalated derivatives can subsequently
be reacted with different electrophiles, as exemplified by
the transformations of 10 and 11 (n-BuLi, Et
to 12 (Scheme 5).
2 2
O, ClPPh )
Enantiopure aminophosphine 12 represents the ppfa
analogue with planar chirality only. Compound 12 was
previously prepared by classical resolution of racemic
p
the product in 79% de and with the (R )-ferrocene
configuration (entry 3), while in diethyl ether the reaction
gave 5 in 80% de but with the (S )-configuration. It is
2,6
precursors with tartaric acid or ephedrine or, alterna-
p
tively, in a diastereoselective manner with (methoxy-
interesting to note that, for all substrates listed, a change
of configuration was found when the reaction was carried
out with t-BuLi in pentane as compared to sec-BuLi in
diethyl ether (entries 2/7, 8/9, 10/11, 12/13).
6
methyl)pyrrolidine as the chiral auxiliary. As is the case
with ppfa, the dimethylamino group of 12 can be ex-
2,3
changed by other nucleophiles, thus allowing further
functional group variations. For example, reaction of 12
The above results guided our choice of chiral auxiliary
and reaction conditions for the subsequent investigations.
Since the O-methylephedrine derivative (1R,2S)-3 gave
with Ac O gave acetate 13 in 90% yield. Acetate 13 is
also directly accessible in 75% yield by reacting 8 with
2
Ac O, thus providing a second route for the replacement
2
superior results with t-BuLi in pentane and with I
2
as
of the chiral auxiliary by a reactive functional group.
the electrophile (entry 7), it was of interest to try
additional electrophiles and to find suitable reaction
conditions to replace the O-methylephedrine unit by
other functional groups.
However, in comparison to the reaction 12 f 13 a higher
temperature and a longer reaction time is required.
The absolute configurations of all intermediates and
products were established by chemical correlation of the
appropriate precursors with (+)- or (-)-10, where the
As shown in Scheme 3, and in a similar way as for I
2
,
6
,7
the use of electrophiles F BrC-CBrF , ClPPh or ben-
2
2
2
configuration is known to be (R ) for (-)-10.
For
p
zophenone gave products 7, 8, and 9 in high chemical
yield (84%, 97%, and 64%, respectively) and with 98%
de. These results indicate that, at least when rather
reactive electrophiles are used, the high diastereoselec-
tivity observed is already established in the initial
lithiation step.
example, the main diastereomer obtained in the reaction
of (1R,2S)-3 with t-BuLi in pentane and iodine, i.e.,
(1R,2S,R )-5 (entry 7), correlates to (-)-10 by the reaction
p
5 f 10. Similar correlations were carried out for the main
products of the reactions given in entries 8, 10, and 12,
i.e., (1S,2S,S )-5, (1R,2S,R )-6, and (1S,2S,S )-6, respec-
p
p
p
Different methods for the replacement of the chiral
auxiliary were tried, and the choice of method depended
on the nature of the ortho-substituent. In the case of iodo-
and bromo-derivatives 5 and 7 (Scheme 4), N-methylation
tively.
Having shown that the chiral auxiliary O-methyl-
ephedrine not only directs ortho-lithiations with very
high diastereoselectivity but also that it can be replaced
easily by other functional groups, we applied this meth-
odology to the synthesis of ferrocenyl diphosphines. As
mentioned above, ferrocenyl diphosphines such as J osi-
phos or Xyliphos (Scheme 1) have been investigated
extensively as ligands in homogeneous catalysts, but only
very recently have Kagan and co-workers reported the
with CH
3
I and subsequent nucleophilic substitution with
(
CH NH led to 2-iodo(bromo)(dimethylaminomethyl)-
3 2
)
6
ferrocenes 10 and 11 in almost quantitative yield (95%
and 93%, respectively). In some respects derivatives 10
and 11 are chemical equivalents of Ugi’s amine (Scheme
1
), since treatment with n-BuLi leads to removal of the

Enantiopure 1,2-Disubstituted Ferrocene Derivatives
J . Org. Chem., Vol. 66, No. 26, 2001 8915
Sch em e 6
ferrocenyl ortho-position with a diastereoselectivity of
9
8%. Replacement of the chiral auxiliary O-methyl-
ephedrine was achieved with dimethylamine, acetate,
diaryl- and dialkylphosphines. As an application, ferro-
cenyl diphosphines possessing planar chirality only were
synthesized in three steps with an overall chemical yield
of up to 77%. Further applications of this methodology,
such as the synthesis of new catalyst ligands based on
biferrocene and biferrocenoazepine backbones, will be
reported in due course.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined on a
1
Kofler melting point apparatus and are uncorrected.
(
H
400.132 MHz), 13C (100.624 MHz) and P (161.975 MHz)
31
NMR spectra were recorded in CDCl . Chemical shifts (δ) are
3
1 13
reported in ppm relative to CHCl
3
(7.26, H), CDCl
3
(77.0, C)
3
1
and 85% H
3
PO
4
(0.0, P). The coupling constants given for
1
3
13
31
C spectra refer to C- P couplings. Mass spectra were
measured on a Finnigan 900S (EI, 70 eV). Optical rotations
were measured on a Perkin-Elmer 241 polarimeter at 20 °C.
All reactions requiring inert conditions were carried out under
synthesis (together with a few catalytic experiments) of
J osiphos analogues lacking central chirality.7 Diphos-
phines with R ) Cy (14), Ph (15), t-Bu, cyclopentyl (and
a P-chiral derivative) were synthesized in 30-52% yield
from enantiopure acetate 13 (Scheme 6). The acetate
precursor 13 was obtained in 6 steps from ferrrocenyl-
carbaldehyde using a chiral acetal as the ortho-directing
group.9
Although the transformation of 13 (accessible in three
steps through the reaction sequence 1 f 3 f 8 f 13) to
diphosphine 149 could be slightly improved (by using
NMP as the solvent and 1.2 equiv of phosphine), a direct
replacement of O-methylephedrine by phosphine was
attempted. Recently, Consiglio, Togni and co-workers
reported that, like J osiphos from ppfa, racemic 14 can
be prepared by reacting racemic 12 with dicyclohexyl-
phosphine in acetic acid.21 By using similar conditions,
not only enantiomerically pure 12 but also 8 could be
transformed to diphosphines 14-16. However, in both
cases a strong dependence of the chemical yields upon
the type of phosphine was observed. The use of dicyclo-
hexylphosphine gave a yield of 81% (14), whereas the use
of diphenylphosphine and bis(3,5-ditrifluoromethyl-
phenyl)phosphine led to lower yields: 28% (15) and 3%
Ar using standard Schlenk techniques. Pentane and Et O were
2
distilled from lithium aluminum hydride, acetonitrile was
distilled from calcium hydride, and THF was distilled from
potassium and benzophenone under Ar prior to use. 1-Methyl-
2
-pyrrolidinone (NMP) was dried over 4Å molecular sieves,
acetic acid and acetic anhydride were freshly distilled, and Ar
was bubbled through each for 12 h prior to use. The mineral
oil present in the potassium hydride (35% in mineral oil) was
removed with hexane. (1R,2S)-Ephedrine and (1S,2S)-pseudo-
ephedrine were used as purchased from Aldrich. Chromato-
graphic separations were performed under gravity either on
silica gel (MERCK, 40-63 µm) or alumina (MERCK, activity
II-III, 0.063-0.200 mm). The enantiomeric purity of amines
1
0 and 11 was established by HPLC (Hewlett-Packard HP1090
liquid chromatograph) on Daicel Chiralcel-OD (250 × 4.6 mm);
eluent 0.2% Et NH, 0.5% 2-PrOH, 99.3% n-hexane, rt. 10: t
), 18.4 (R ) min. 11: t 15.6 (S ), 19.3 (R ) min.
(1R ,2S )-N -M e t h y l-1-m e t h o x y -1-p h e n y lp r o p -2-y l-
2
R
1
4.3 (S
p
p
R
p
p
1
9,22
a m in e [(1R,2S)-O-Meth ylep h ed r in e, (1R,2S)-1].
A dried
2
-L three-necked round-bottomed flask was charged with
potassium hydride (11.0 g, 275 mmol) and THF (300 mL). To
this suspension was added dropwise a solution of (1R,2S)-
ephedrine (32.5 g, 197 mmol) in THF (300 mL) at room
temperature within 2 h. The reaction mixture was stirred for
1
3
6 h, and a solution of CH I (26.7 g, 188 mmol) in THF (200
(16), respectively. In contrast to ppfa, only very nucleo-
mL) was added dropwise. After stirring for a further 16 h the
reaction was carefully quenched by the addition of ice/water
(200 mL). The organic phase was separated, and the aqueous
philic phosphines seem to react efficiently under the
given reaction conditions. In summary, the chiral
auxiliary can be replaced not only by dimethylamine
or acetate but also by certain phosphines, thus allowing
the synthesis of 14 (and analogues) in three steps from
O-methylephedrine (1) and commercially available
phase was extracted with Et
organic layers were washed with brine, dried over MgSO
2
O (3 × 300 mL). The combined
4
, and
concentrated in vacuo. The residue was distilled under reduced
pressure to give the product, which distilled over at 78 °C (1
1
Torr) as a colorless liquid (30.5 g, 86%). H NMR δ: 1.02 (d, J
2 3 3
[FcCH N(CH ) ]I, through the reaction sequence 1 f 3
)
6.3 Hz, 3H), 1.26 (br s, 1H), 2.38 (s, 3H), 2.72 (dq, J ) 5.0
f 8 f 14, in up to 77% (14) overall yield.
and 6.3 Hz, 1H), 3.26 (s, 3H), 4.13 (d, J ) 5.0 Hz, 1H), 7.25-
7
6
.32 (m, 3H), 7.33-7.37 (m, 2H). 13C NMR δ: 14.8, 33.9, 57.2,
0.0, 86.3, 127.3, 127.5, 128.3, 139.7. MS (20 °C) m/z: 179 (0.3)
Con clu sion
+
[M ], 121 (5), 105 (5), 58 (100). HRMS: calcd for C11
H
17ON
2
0
In conclusion, we have identified O-methylephedrine
as a very versatile and efficient chiral auxiliary for the
ortho-lithiation of ferrocene. Reaction of N-ferrocenyl-
methyl-O-methylephedrine, (1R,2S)-3, with t-BuLi in
pentane followed by treatment with electrophiles allowed
the introduction of different functional groups into the
179.1310, found 179.1314. [R]
[
D
) -86.8 (c ) 1.0, CH Cl ) [lit.:
2 2
2
0
19a
R]
D
3
) -84.4 (c ) 1.0, CHCl )].
(
1S ,2S )-N -M e t h y l-1-m e t h o x y -1-p h e n y lp r o p -2-y l-
2
0,22
am in e [(1S,2S)-O-Meth yl-pseu do-eph edr in e, (1S,2S)-1].
1S,2S)-1 was prepared from (1S,2S)-pseudo-ephedrine (7.0 g,
.2 mmol) using the same procedure as described above for
1R,2S)-1. The product distilled at 94 °C (1 Torr) as a colorless
(
4
(
1
liquid (4.9 g, 64%). H NMR δ: 0.74 (d, J ) 6.3 Hz, 3H), 2.40
(21) (a) Bronco, S.; Consiglio, G.; Di Benedetto, S.; Fehr, M.;
(s, 3H), 2.72 (dq, J ) 6.3 and 8.3 Hz, 1H), 3.15 (s, 3H), 3.83 (d,
Spindler, F.; Togni, A. Helv. Chim. Acta 1995, 78, 883. (b) Bronco, S.;
Consiglio, G.; Di Benedetto, S.; Drent, E.; Heeres, H. J . (Shell
Internationale Research Maatschappij B.V., Netherlands) Brit. UK Pat.
Appl. GB 2289855 A1 19951206, 1995.
13
J ) 8.3 Hz, 1H), 7.24-7.37 (m, 5H). C NMR δ: 15.0, 33.3,
(22) The procedure described in ref 19a was slightly modified.

8
916 J . Org. Chem., Vol. 66, No. 26, 2001
Xiao et al.
5
1
C
CH
6.3, 59.8, 87.9, 127.5, 127.6, 127.9, 139.2. MS (20 °C) m/z:
(1R,2S)-N-F er r ocen ylm eth yl-N-m eth yl-1-cycloh exyl-1-
m eth oxyp r op -2-yla m in e [(1R,2S)-4]. (1R,2S)-4 was ob-
tained as a red oil (3.52 g, 92% yield) from (1R,2S)-2 (2.04 g).
+
79 (1) [M ], 121 (27), 105 (17), 58 (100). HRMS: calcd for
2
0
11
H
17ON 179.1310, found 179.1315. [R]
D
) +105.0 (c ) 2.0,
2
0
20
1
2
Cl
2
) [lit. for (1R,2R)-1: [R]
D
) -104.5 (c ) 1.7, THF)].
1R,2S)-N-Met h yl-1-cycloh exyl-1-m et h oxyp r op -2-yl-
H NMR δ: 0.95 (d, J ) 6.6 Hz, 3H), 0.99-1.26 (m, 5H), 1.49-
(
1.75 (m, 6H), 2.10 (s, 3H), 2.71 (dq, J ) 7.6 and 6.6 Hz, 1H),
2.81 (dd, J ) 3.6 and 7.6 Hz, 1H), 3.30 (d, J ) 12.9 Hz, 1H),
3.38 (d, J ) 12.9 Hz, 1H), 3.42 (s, 3H), 4.07 (m, 2H), 4.10 (s,
5H), 4.12 (m, 1H), 4.16 (m, 1H). 13C NMR δ: 8.4, 26.5, 26.7,
26.7, 26.9, 30.7, 36.7, 39.9, 54.2, 57.5, 60.8, 67.6, 67.7, 68.4,
a m in e [(1R,2S)-2]. A 100-mL autoclave with a glass inlet was
charged with (1R,2S)-O-methylephedrine, (1R,2S)-1, (3.0 g,
1
6.8 mmol), RuO
2 2
(170 mg, 1.3 mmol), EtOH (25 mL) and H O
(25 mL). The suspension was hydrogenated for 2 h at 90 °C
+
under a hydrogen pressure of 90 bar. The mixture was cooled
to room temperature, and the catalyst was removed by
filtration over a layer of Celite. Ethanol was removed under
reduced pressure, and the aqueous phase was extracted with
69.7, 70.0, 85.5, 88.8. MS (80 °C) m/z: 383 (4) [M ], 256 (17),
199 (100). HRMS: calcd for C22
383.1901. [R]20
) +11.0 (589 nm), +11.4 (578 nm), +13.6 (546
nm) (c ) 1.0, CH Cl ).
H33ONFe 383.1912, found
λ
2
2
CH
2
Cl
2
(6 × 20 mL). The combined organic layers were washed
(1S,2S)-N-F er r ocen ylm eth yl-N-m eth yl-1-cycloh exyl-1-
m eth oxyp r op -2-yla m in e [(1S,2S)-4]. (1S,2S)-4 was obtained
from (1S,2S)-2 (2.04 g). Chromatography on silica with PE/
with brine and dried over MgSO
in vacuo. The residue was purified by Kugelrohr distillation
at 150 °C (1 Torr) to give the product as a colorless liquid (2.3
4
, and the solvent was removed
2 3
Et O/Et N (30/3/1) as eluent gave the desired product as a red
1
1
g, 74%). H NMR δ: 1.00 (d, J ) 6.6 Hz, 3H), 0.94-1.77 (m,
oil (2.87 g, 75%). H NMR δ: 0.91 (d, J ) 6.8 Hz, 3H), 1.00-
1.28 (m, 5H), 1.51-1.80 (m, 6H), 2.15 (s, 3H), 2.68 (dd, J )
6.0 and 5.8 Hz, 1H), 2.81 (dq, J ) 6.0 and 6.8 Hz, 1H), 3.30 (d,
J ) 13.1 Hz, 1H), 3.45 (s, 3H), 3.51 (d, J ) 13.1 Hz, 1H), 4.06
1
6
1H), 1.92-1.96 (m, 1H), 2.42 (s, 3H), 2.66 (dq, J ) 3.5 and
.6 Hz, 1H), 2.90 (dd, J ) 3.5 and 7.6 Hz, 1H), 3.48 (s, 3H).
C NMR δ: 13.7, 26.1, 26.2, 26.5, 29.4, 29.9, 34.0, 40.6, 56.1,
1
3
+
13
6
1.51, 88.6. MS (20 °C) m/z: 185 (1) [M ], 127 (2), 95 (4), 58
(m, 2H), 4.09 (s, 5H), 4.14 (m, 1H), 4.19 (m, 1H). C NMR δ:
(
100). HRMS: calcd for C11
H
23ON 185.1780, found 185.1778.
Cl ).
1S,2S)-N-Met h yl-1-cycloh exyl-1-m et h oxyp r op -2-yl-
a m in e [(1S,2S)-2]. (1S,2S)-O-Methyl-pseudo-ephedrine, (1S,
S)-1, (2.0 g, 12.1 mmol) was hydrogenated as described above
for (1R,2S)-2 to give (1S,2S)-2 as a colorless liquid (150 °C at
9.1, 26.4, 26.5, 26.7, 27.9, 30.4, 37.2, 40.4, 54.9, 58.3, 61.8, 67.4,
2
0
+
[R]
D
) -6.1 (c ) 1.0, CH
2
2
67.5, 68.4, 69.8, 69.8, 86.1, 89.7. MS (60 °C) m/z: 383 (3) [M ],
(
256 (11), 199 (100). HRMS: calcd for C22
found 383.1924. [R]20
) +2.8 (589 nm), +2.7 (578 nm), +2.0
(546 nm) (c ) 2.0, CH Cl ).
H33ONFe 383.1912,
λ
2
2
2
P r ep a r a tion of Der iva tives 5 a n d 6. Gen er a l P r oce-
d u r e. To a degassed solution of each diastereomer of 3 or 4 (1
mmol) in 10 mL of an anhydrous solvent (Et O, THF or
2
1
1
1
Torr, 1.7 g, 80%). H NMR δ: 0.93 (d, J ) 6.0 Hz, 3H), 1.00-
.24 (m, 6H), 1.46-1.66 (m, 6H, CH ), 2.31 (s, 3H), 2.55 (dq, J
4.0 and 6.0 Hz, 1H), 2.62 (dd, J ) 6.0 and 7.0 Hz, 1H), 3.48
2
)
pentane) was added dropwise BuLi (either 0.75 mL of a 1.6 M
solution of n-BuLi in hexane or 0.92 mL of a 1.3 M solution of
sec-BuLi in cyclohexane or 0.71 mL of a 1.7 M solution of
t-BuLi in pentane, 1.2 mmol) under Ar at -78 °C. The reaction
mixture was stirred for 1.5 h at -78 °C and then for 2.5 h
(pentane) or 1.5 h (ether) at -30 °C, during which time the
yellow suspension turned orange. The temperature was again
lowered to -78 °C, and a solution of iodine (381 mg, 1.5 mmol)
in THF (5 mL) was added dropwise; stirring was continued at
this temperature for additional 20 min. The reaction was
1
3
(
s, 3H). C NMR δ: 16.0, 26.3, 26.5, 26.6, 27.1, 31.0, 33.9,
+
40.1, 56.1, 61.6, 90.7. MS (20 °C) m/z: 185 (4) [M ], 127 (4),
95 (8), 58 (100). HRMS: calcd for C11 23ON 185.1780, found
1 Cl ).
P r ep a r a tion of Der iva tives 3 a n d 4. Gen er a l P r oce-
d u r e. A degassed suspension of N-ferrocenylmethyl-N,N,N-
H
2
0
85.1775. [R]
D
) +19.3 (c ) 1.0, CH
2
2
2
3
trimethylammonium iodide (3.85 g, 10 mmol) and the
appropriate diastereomer of amine 1 or 2 (11 mmol) in
anhydrous acetonitrile (100 mL) was refluxed under Ar for 3-4
days progress of the reaction was monitored by TLC). After
the reaction mixture cooled to room temperature, the solvent
was evaporated under reduced pressure, and the residue was
quenched with saturated NaHCO
was separated, and the aqueous layer was extracted three
times with Et O (20 mL). The combined organic layers were
washed with aqueous Na and brine and dried over
MgSO . After removal of the solvent the residue was purified
3
(10 mL), the organic phase
2
purified by chromatography on silica with PE/Et
/1) as eluent, except where stated otherwise.
1R,2S)-N-F er r ocen ylm et h yl-N-m et h yl-1-m et h oxy-1-
2
O/Et
3
N (10/
2 2 3
S O
3
4
(
by chromatography on silica gel with PE/Et
1) as eluent, unless stated otherwise.
2 3
O/Et N (100/20/
p h en ylp r op -2-yla m in e [(1R,2S)-3]. This reaction was also
carried out on a 50-mmol scale; (1R,2S)-3 was obtained as a
red oil (17.0 g, 90%) from (1R,2S)-1 (9.85 g, 55 mmol). H NMR
δ: 1.03 (d, J ) 6.8 Hz, 3H), 2.27 (s, 3H), 2.84 (dq, J ) 4.6 and
6
(1R ,2S ,R
m eth oxy-1-p h en ylp r op -2-yla m in e [(1R,2S,R
action was also carried out on a 20-mmol scale. (1R,2S,R
p
)-N -(2-Iod ofe r r oce n ylm e t h yl)-N -m e t h yl-1-
)-5]. This re-
)-5
1
p
p
.8 Hz, 1H), 3.28 (s, 3H), 3.43 (d, J ) 13.1 Hz, 1H), 3.51 (d, J
was obtained as the major product when (1R,2S)-3 (7.54 g, 20
mmol) was reacted in pentane with t-BuLi. Chromatography
)
13.1 Hz, 1H), 4.09 (m, 4H), 4.11 (s, 5H), 4.29 (d, J ) 4.6 Hz,
1
3
1
H), 7.24-7.29 (m, 3H), 7.33-7.37 (m, 2H). 13C NMR δ: 8.4,
2 3 p
with PE/Et O/Et N (100/20/3) gave (1R,2S,R )-5 as a red oil
1
7.9, 53.9, 56.7, 62.4, 67.6, 67.8, 68.4, 69.7, 69.9, 85.1, 85.6,
(9.1 g, 90%, 98% de). H NMR δ: 1.07 (d, J ) 6.8 Hz, 3H),
2.25 (s, 3H), 2.90 (dq, J ) 4.8 and 6.8 Hz, 1H), 3.27 (s, 3H),
3.46 (d, J ) 13.6 Hz, 1H), 3.50 (d, J ) 13.6 Hz, 1H), 4.07 (s,
5H), 4.09 (m, 1H), 4.13 (m, 1H), 4.29 (d, J ) 4.8 Hz, 1H), 4.38
+
27.0, 127.0, 128.0, 141.3. MS (80 °C) m/z: 377 (3) [M ], 256
(12), 199 (100). HRMS: calcd for C22
H
27ONFe 377.1442, found
2
0
3
77.1436. [R] ) -8.7 (589 nm), -8.1 (578 nm), -6.5 (546
λ
1
8
13
nm) (c ) 1.0, CH
2
Cl
2
) (corrected value ).
(m, 1H), 7.22-7.27 (m, 3H), 7.30-7.34 (m, 2H). C NMR δ:
(
1S,2S)-N-F er r ocen ylm et h yl-N-m et h yl-1-m et h oxy-1-
9.2, 37.1, 45.7, 54.2, 56.7, 63.5, 68.5, 68.7, 71.5, 74.4, 85.2, 86.5,
+
p h en ylp r op -2-yla m in e [(1S,2S)-3]. (1S,2S)-3 was prepared
from (1S,2S)-1 (1.97 g). Chromatography on silica gel with PE/
127.0, 127.0, 128.0, 141.5. MS (80 °C) m/z: 503 (1) [M ], 382
(23), 325 (100). HRMS: calcd for C22
503.0419. [R]20
) -35.7 (589 nm), -38.3 (578 nm), -52.6 (546
nm) (c ) 2.0, CH Cl ).
(1R ,2S ,S )-N -(2-Iod ofe r r oce n ylm e t h yl)-N -m e t h yl-1-
m eth oxy-1-p h en ylp r op -2-yla m in e [(1R,2S,S )-5]. (1R,
2S,S )-5 was obtained as the main product when (1R,2S)-3
(377 mg) was reacted in diethyl ether with sec-BuLi. Chro-
matography with PE/Et O/Et N (100/20/3) as the eluent
yielded the product as a red oil (297 mg, 59%, 80% de).
H26ONFeI 503.0408, found
Et
yellow solid (2.64 g, 70% yield). Mp: 31 °C. H NMR δ: 0.66
d, J ) 6.8 Hz, 3H), 2.30 (s, 3H), 3.03 (dq, J ) 8.6 and 6.8 Hz,
H), 3.17 (s, 3H), 3.44 (d, J ) 12.9 Hz, 1H), 3.66 (d, J ) 12.9
Hz, 1H), 4.05 (d, J ) 8.6 Hz, 1H), 4.07-4.10 (m, 2H), 4.11 (s,
H), 4.17 (m, 1H), 4.25 (m, 1H), 7.24-7.29 (m, 3H), 7.31-7.35
2
O/Et
3
N (30/3/1) as eluent gave the desired product as a
λ
1
2
2
(
1
p
p
p
5
1
3
(
6
m, 2H). C NMR δ: 11.7, 37.3, 54.0, 56.4, 61.6, 67.6, 67.9,
2
3
1
8.4, 69.9, 70.0, 85.6, 86.6, 127.5, 127.8, 128.2, 140.9. MS (80
H
+
°
C
C) m/z: 377 (2) [M ], 256 (7), 199 (100). HRMS: calcd for
27ONFe 377.1442, found 377.1429. [R]20
) +76.3 (589
nm), +79.7 (578 nm), +94.3 (546 nm) (c ) 1.0, CH Cl ).
NMR δ: 1.08 (d, J ) 6.7 Hz, 3H), 2.24 (s, 3H), 2.83 (dq, J )
5.3 and 6.7 Hz, 1H), 3.24 (s, 3H), 3.42 (d, J ) 13.2 Hz, 1H),
3.48 (d, J ) 13.2 Hz, 1H), 4.03 (m, 1H), 4.07 (s, 5H), 4.12 (m,
22
H
λ
2
2
1
7
H), 4.24 (d, J ) 5.3 Hz, 1H), 4.36 (m, 1H), 7.20-7.25 (m, 3H),
.29-7.34 (m, 2H). 13C NMR δ: 8.4, 37.6, 46.2, 53.7, 56.7, 62.6,
(23) Lednicer, D.; Hauser, C. R. Organic Syntheses; Wiley: New
York, 1973; Collect. Vol. V, p 434.
68.8, 68.9, 71.5, 74.3, 84.5, 86.4, 127.0, 127.1, 128.0, 141.4. MS

Enantiopure 1,2-Disubstituted Ferrocene Derivatives
J . Org. Chem., Vol. 66, No. 26, 2001 8917
+
(
80 °C) m/z: 503 (2) [M ], 382 (38), 325 (100). HRMS: calcd
2S,S
p
)-6 was obtained as the major product when (1S,2S)-4
2
0
for C22
H
26ONFeI 503.0408, found 503.0421. [R]
λ
) +0.2 (589
Cl ).
)-N -(2-Iod ofe r r oce n ylm e t h yl)-N -m e t h yl-1-
m eth oxy-1-p h en ylp r op -2-yla m in e [(1S,2S,R )-5]. (1S,
S,R )-5 was obtained as the major product when (1S,2S)-3
377 mg) was reacted in pentane with t-BuLi. Red oil (317 mg,
2
(383 mg) was reacted in Et O with sec-BuLi. Red oil (199 mg,
1
nm), +2.6 (578 nm), +11.4 (546 nm) (c ) 0.5, CH
2
2
39%, 16% de). H NMR δ: 0.99 (d, J ) 6.6 Hz, 3H), 0.84-1.84
(m, 11H), 2.20 (s, 3H), 2.67 (t, J ) 6.1 Hz, 1H), 2.89 (dq, J )
6.1 and 6.6 Hz, 1H), 3.31 (d, J ) 13.4 Hz, 1H), 3.46 (s, 3H),
3.61 (d, J ) 13.4 Hz, 1H), 4.10 (s, 5H), 4.16 (m, 1H), 4.35 (m,
1H), 4.37 (m, 1H). 13C NMR δ: 9.3, 26.4, 26.5, 26.7, 28.1, 30.4,
36.9, 40.3, 45.9, 54.4, 57.6, 62.0, 68.5, 69.1, 71.6, 74.2, 87.3,
(
1S ,2S ,R
p
p
2
(
6
3
1
(
(
6
°
p
1
3%, 49% de). H NMR δ: 0.72 (d, J ) 6.6 Hz, 3H), 2.30 (s,
H), 3.12-3.20 (m, 1H), 3.17 (s, 3H), 3.62 (d, J ) 13.6 Hz,
H), 3.72 (d, J ) 13.6 Hz, 1H), 4.11 (d, J ) 8.6 Hz, 1H), 4.12
s, 5H), 4.17 (m, 1H), 4.29 (m, 1H), 4.40 (m, 1H), 7.26-7.36
m, 5H). C NMR δ: 13.4, 36.2, 45.8, 55.6, 56.4, 63.7, 68.5,
8.9, 71.5, 74.6, 86.0, 86.6, 127.6, 127.8, 128.2, 141.0. MS (70
+
90.3. MS (70 °C) m/z: 509 (3) [M ], 382 (21), 325 (100).
2
0
HRMS: calcd for C22
) +30.5 (589 nm), +32.8 (578 nm), +45.4 (546 nm) (c ) 1.0,
CH CN).
H32ONFeI 509.0878, found 509.0891. [R]
λ
13
3
P r ep a r a tion of Der iva tives 7-9. Gen er a l P r oced u r e.
(1R,2S)-3 was reacted in pentane with t-BuLi and quenched
with the appropriate electrophile as described in the general
+
C) m/z: 503 (2) [M ], 382 (21), 325 (100). HRMS: calcd for
26ONFeI 503.0408, found 503.0391. [R]20
) +51.8 (589
nm), +53.0 (578 nm), +53.0 (546 nm) (c ) 2.0, CH Cl ).
1S,2S,S )-N-(2-Iodofer r ocen ylm eth yl)-N-m eth yl-1-m eth -
oxy-1-p h en ylp r op -2-yla m in e [(1S,2S,S )-5]. (1S,2S,S )-5
was obtained as the major product when (1S,2S)-3 (377 mg)
was reacted in Et O with sec-BuLi. Red oil (262 mg, 52%, 64%
de). H NMR δ: 0.75 (d, J ) 6.8 Hz, 3H), 2.32 (s, 3H), 2.99
dq, J ) 6.8 and 8.4 Hz, 1H), 3.20 (s, 3H), 3.50 (d, J ) 13.4
Hz, 1H), 3.71 (d, J ) 13.4 Hz, 1H), 4.09-4.12 (m, 1H), 4.11 (s,
C
22
H
λ
2
2
p
preparation procedure for (1R,2S,R )-5. In the cases of 8 and
(
p
9, after addition of the electrophile the reaction mixture was
allowed to warm to room temperature and stirring was
continued for 16 h before workup. The workup procedure was
similar to that described for 5. Products (1R,2S,R
9 were purified by chromatography on silica with PE/Et
p
p
2
p
)-7, 8, and
O/
1
2
(
Et
3
N (100/20/1) as the eluent, unless stated otherwise.
(1R,2S,R
p
)-N-(2-Br om ofer r ocen ylm eth yl)-N-m eth yl-1-
)-7]. Reaction
of (1R,2S)-3 (4.54 g, 12 mmol) and 1,2-dibromotetrafluoro-
ethane (4.69 g, 18 mmol) gave (1R,2S,R )-7 as a red oil (4.60
5
5
7
H), 4.18 (m, 1H), 4.35 (m, 1H), 4.39 (m, 1H), 7.25-7.35 (m,
m eth oxy-1-p h en ylp r op -2-yla m in e [(1R,2S,R
p
1
3
H). C NMR δ: 12.0, 37.6, 46.2, 53.4, 56.5, 61.9, 68.9, 69.0,
1.5, 74.3, 86.7, 86.8, 127.6, 127.8, 128.2, 140.9. MS (70 °C)
p
+
1
m/z: 503 (2) [M ], 382 (27), 325 (100). HRMS: calcd for C22
H
26
-
g, 84%, 98% de). H NMR δ: 1.06 (d, J ) 6.8 Hz, 3H), 2.26 (s,
3H), 2.90 (dq, J ) 4.6 and 6.8 Hz, 1H), 3.27 (s, 3H), 3.49 (d, J
) 13.6 Hz, 1H), 3.63 (d, J ) 13.6 Hz, 1H), 4.03 (m, 1H), 4.05
(m, 1H), 4.10 (s, 5H), 4.30 (d, J ) 4.6 Hz, 1H), 4.37 (m, 1H),
7.23-7.26 (m, 3H), 7.30-7.34 (m, 2H). 13C NMR δ: 9.0, 37.4,
52.4, 56.7, 63.7, 66.0, 68.2, 70.0, 71.0, 80.3, 84.2, 85.3, 126.9,
2
0
ONFeI 503.0408, found 503.0387. [R]
69.3 (578 nm), +87.2 (546 nm) (c ) 1.0, CH
1R,2S,R )-N-(2-Iod ofer r ocen ylm eth yl)-N-m eth yl-1-cy-
cloh exyl-1-m eth oxyp r op -2-yla m in e [(1R,2S,R )-6]. (1R,
S,R )-6 was obtained as the major product when (1R,2S)-4
383 mg) was reacted in Et O with sec-BuLi. Chromatography
eluent PE/Et O/Et N (80/20/1). Red oil (81 mg, 16%, 17% de).
H NMR δ: 0.99 (d, J ) 6.3 Hz, 3H), 0.88-1.26 (m, 6H), 1.51-
.74 (m, 5H), 2.14 (s, 3H), 2.74 (dq, J ) 6.3 and 8.3 Hz, 1H),
.79 (dd, J ) 2.8 and 8.3 Hz, 1H), 3.36 (d, J ) 13.2 Hz, 1H),
.40 (d, J ) 13.2 Hz, 1H), 3.41 (s, 3H), 4.09 (s, 5H), 4.14 (m,
H), 4.18 (m, 1H), 4.19 (m, 1H). C NMR δ: 8.5, 26.1, 26.5,
6.8, 26.9, 30.8, 36.4, 39.5, 45.8, 54.3, 56.5, 60.9, 68.4, 69.2,
λ
) +65.6 (589 nm),
+
2
2
Cl ).
(
p
p
2
(
p
+
2
128.0, 126.9, 141.5. MS (50 °C) m/z: 457/455 (1) [M ], 336/
2
3
334 (22), 279/277 (100). HRMS: calcd for C22
H
26ONFeBr
) -45.3 (589 nm), -48.4 (578
nm), -60.6 (546 nm) (c ) 0.66, CHCl ).
(1R,2S,R )-N-(2-Diph en ylp h osph in ofer r ocen ylm eth yl)-
N-m eth yl-1-m eth oxy-1-ph en ylpr op-2-ylam in e [(1R,2S,R )-
8]. (1R,2S)-3 (3.77 g, 10 mmol) and chlorodiphenylphosphine
(3.32 g, 15 mmol) yielded (1R,2S,R )-8 as an orange viscous
1
20
455.0547, found 455.0556. [R]
λ
1
2
3
1
2
7
3
3
p
p
1
3
p
+
1
1.4, 74.7, 86.5, 88.7. MS (70 °C) m/z: 509 (2) [M ], 382 (14),
oil (5.44 g, 97%, 98% de). H NMR δ: 0.79 (d, J ) 6.8 Hz, 3H),
2.01 (s, 3H), 2.75 (dq, J ) 3.8 and 6.8 Hz, 1H), 3.22 (s, 3H),
3.44 (d, J ) 13.4 Hz, 1H), 3.74 (m, 1H), 3.79 (dd, J ) 1.5 and
13.4 Hz, 1H), 3.94 (s, 5H), 4.18 (m, 2H), 4.29 (m, 1H), 7.17-
7.26 (m, 8H), 7.30-7.37 (m, 5H), 7.54-7.58 (m, 2H). C NMR
δ: 8.2, 36.4, 53.7 (d, J ) 8.4 Hz), 56.5, 64.4, 68.7, 69.6, 71.3
(d, J ) 4.6 Hz), 72.7 (d, J ) 4.6 Hz), 75.7 (d, J ) 8.4 Hz), 85.2,
92.2 (d, J ) 24.3 Hz), 126.7, 126.8, 127.5, 127.7 (d, J ) 6.1
Hz), 128.0, 128.0, 128.9, 132.5 (d, J ) 18.2 Hz), 135.1 (d, J )
21.3 Hz), 138.1 (d, J ) 8.4 Hz), 140.2 (d, J ) 9.9 Hz), 142.0.
25 (64), 85 (100). HRMS: calcd for C22
H
32ONFeI 509.0878,
) +11.8 (589 nm), +11.2 (578 nm), +5.1
Cl ).
)-N-(2-Iod ofer r ocen ylm eth yl)-N-m eth yl-1-cy-
cloh exyl-1-m eth oxyp r op -2-yla m in e [(1R,2S,S )-6]. (1R,
S,S )-6 was obtained as the major product when (1R,2S)-4
383 mg) was reacted in pentane with t-BuLi. Chromatography
eluent PE/Et O/Et N (80/20/1). Red oil (392 mg, 77%, 78% de).
H NMR δ: 1.02 (d, J ) 6.7 Hz, 3H), 0.88-1.26 (m, 6H), 1.52-
2
0
found 509.0854. [R]
(
λ
546 nm) (c ) 2.0, CH
2
2
1
3
(
1R,2S,S
p
p
2
(
p
2
3
1
3
1
+
1
2
3
1
2
7
3
.76 (m, 5H), 2.10 (s, 3H), 2.72 (dq, J ) 6.7 and 7.6 Hz, 1H),
.80 (dd, J ) 2.8 and 7.6 Hz, 1H), 3.38 (d, J ) 13.2 Hz, 1H),
.41 (d, J ) 13.2 Hz, 1H), 3.42 (s, 3H), 4.10 (s, 5H), 4.17 (m,
H), 4.26 (m, 1H), 4.39 (m, 1H). C NMR δ: 8.5, 26.4, 26.5,
6.7, 26.9, 31.1, 36.4, 39.5, 46.0, 54.3, 57.7, 70.0, 68.7, 69.1,
P NMR δ: -22.0. MS (150 °C) m/z: 561 (2) [M ], 440 (24),
383 (100). HRMS: calcd for C34 36ONFeP 561.1884, found
561.1878. [R]20
) +213.7 (589 nm), +225.6 (578 nm), +278.5
(546 nm) (c )1.0, CH Cl ).
(1R,2S,R )-N-[2-(Dip h en yl-h yd r oxym eth yl)fer r ocen yl-
m et h yl]-N-m et h yl-1-m et h oxy-1-p h en ylp r op -2-yla m in e
[(1R,2S,R )-9]. (1R,2S)-3 (377 mg, 1.0 mmol) and a solution
of benzophenone (273 mg, 1.5 mmol) in THF (5 mL) gave
(1R,2S,R )-9 as an orange viscous oil (376 mg, 64%, 98% de).
H
λ
1
3
2
2
p
+
1.5, 74.5, 86.6, 89.1. MS (70 °C) m/z: 509 (2) [M ], 382 (13),
25 (77), 83 (100). HRMS: calcd for C22
H
32ONFeI 509.0878,
) +25.8 (589 nm), +27.7 (578 nm),
Cl ).
)-N-(2-Iod ofer r ocen ylm eth yl)-N-m eth yl-1-cy-
cloh exyl-1-m et h oxyp r op -2-yla m in e [(1S,2S,R )-6]. (1S,
S,R )-6 was obtained as the major product when (1S,2S)-4
383 mg) was reacted in pentane with t-BuLi. Red oil (249 mg,
p
2
0
found 509.0887. [R]
+
λ
37.4 (546 nm) (c ) 2.0, CH
2
2
p
1
(
1S,2S,R
p
H NMR δ: 0.85 (d, J ) 6.8 Hz, 3H), 1.56 (br s, 1H), 2.11 (s,
3H), 2.76 (dq, J ) 2.0 and 6.8 Hz, 1H), 3.03 (d, J ) 13.6 Hz,
1H), 3.19 (s, 3H), 3.79 (d, J ) 13.6 Hz, 1H), 3.83 (m, 1H), 3.93
(s, 5H), 4.08 (m, 2H), 4.22 (m, 1H), 7.10-7.36 (m, 12 H), 7.47-
p
2
(
4
(
6
3
1
3
8
p
1
13
9%, 40% de). H NMR δ: 0.94 (d, J ) 6.8 Hz, 3H), 0.98-1.79
7.60 (m, 3H). C NMR δ: 6.9, 36.3, 52.1, 56.6, 63.0, 65.4, 69.8,
m, 11H), 2.20 (s, 3H), 2.66 (t, J ) 6.1 Hz, 1H), 2.89 (dq, J )
70.7, 70.8, 77.7, 82.7, 83.9, 126.2, 126.4, 126.5, 127.0, 127.3,
127.4, 127.6, 128.1, 130.1, 140.9, 147.7, 149.9 (2 C signals not
determined). MS (150 °C) m/z: 559 (5) [M + 1], 438 (31), 381
37 2
(96), 243 (100). HRMS: calcd for C35H O NFe 558.2174, found
.1 and 6.8 Hz, 1H), 3.43 (s, 3H), 3.44 (d, J ) 13.4 Hz, 1H),
.48 (d, J ) 13.4 Hz, 1H), 4.09 (s, 5H), 4.16 (m, 1H), 4.26 (m,
+
1
3
H), 4.38 (m, 1H). C NMR δ: 9.3, 26.4, 26.6, 26.7, 27.9, 30.4,
6.3, 40.3, 46.0, 55.8, 57.8, 61.9, 68.4, 68.9, 71.5, 74.4, 86.9,
558.2248. [R]20
(546 nm) (c ) 1.0, CH
(R )-1-Iod o-2-(d im eth yla m in om eth yl)fer r ocen e [(R
10]. To a solution of (1R,2S,R )-5 (8.57 g, 17 mmol) in CH CN
(60 mL) was added CH I (4.83 g, 34 mmol). After the mixture
stirred for 30 min at room temperature, Et O (300 mL) was
added slowly. The resulting yellow precipitate was filtered off
λ
) +155.7 (589 nm), +168.1 (578 nm), +232.3
+
9.8. MS (70 °C) m/z: 509 (3) [M ], 382 (23), 325 (100).
2
Cl ).
2
HRMS: calcd for C22
)
Cl
H
32ONFeI 509.0878, found 509.0864. [R]20
λ
p
p
)-
-8.7 (589 nm), -9.7 (578 nm), -20.0 (546 nm) (c ) 1.0, CH
).
1S,2S,S
cloh exyl-1-m et h oxyp r op -2-yla m in e [(1S,2S,S
2
-
p
3
2
3
(
p
)-N-(2-Iod ofer r ocen ylm eth yl)-N-m eth yl-1-cy-
)-6]. (1S,
2
p

8
918 J . Org. Chem., Vol. 66, No. 26, 2001
Xiao et al.
and dried in vacuo [10.5 g, 96% yield, mp 183 °C (dec)]. The
dry ammonium iodide salt, 40% aqueous dimethylamine
solution (100 mL) and benzene (100 mL) were placed in a 500-
mL steel autoclave and heated to 110 °C for 16 h. After the
reaction cooled to room temperature, the benzene layer was
separated, and the aqueous phase was extracted with three
(R
p
)-2-[(Dicycloh exylp h osp h in o)m et h yl]-1-d ip h en yl-
p h osp h in ofer r ocen e [(R
cyclohexylphosphine (238 mg) as nucleophile. From (R
heating at 130 °C for 12 h. From (R )-12: heating at 100 °C
for 40 h. Chromatography with PE (to remove unreacted
phosphine) followed by PE/Et O (25/1) as eluent gave the
product as a yellow solid [479 mg, 81% yield from both (R )-8
and (R )-12]. From (R )-13: a solution of (R )-13 (442 mg, 1
mmol) in 1-methyl-2-pyrrolidinone (NMP) (5 mL) was de-
gassed, and dicyclohexylphosphine (238 mg, 1.2 mmol) was
added by syringe. The resulting mixture was degassed again
and heated to 130 °C for 60 h. Subsequently, the reaction
mixture was cooled to room temperature, washed with satu-
p
)-14]. From (R
p
)-8 or (R
p
)-12: di-
p
)-8:
p
2
portions of Et
washed with water and brine and dried with MgSO
removal of the solvent, the residue was purified by chroma-
tography on silica gel. Elution with PE/Et O/Et N (10/10/1)
afforded (R )-10 as a red oil [5.92 g, 99% yield; 95% overall
based on (1R,2S,R )-5] in >99% ee as determined by HPLC.
)-1-Br om o-2-(dim eth ylam in om eth yl)fer r ocen e [(R )-
1]. (R )-11 was prepared in exactly the same way as (R )-10
see above) starting from (1R,2S,R )-7 (4.32 g, 9.5 mmol). The
respective ammonium iodide intermediate was obtained as a
yellow solid (5.42 g, 96% yield, mp 178 °C). Product (R )-11
was isolated as a red liquid [2.83 g, 97% yield; 93% based on
1R,2S,R )-7] in >99% ee as determined by HPLC.
)-1-Dip h en ylp h osp h in o-2-(d im eth yla m in om eth yl)-
fer r ocen e [(R )-12]. To a solution of (R )-10 (2.58 g, 7 mmol)
or (R )-11 (2.25 g, 7 mmol) in Et O (70 mL) was added n-BuLi
5.3 mL of a 1.6 M solution in hexane, 8.5 mmol) at -40 °C,
and the resulting mixture was stirred for 2 h. Subsequently,
Ph
2
O (50 mL). The combined organic layers were
p
4
. After
p
p
p
2
3
p
p
(
R
p
p
1
p
p
4 4
rated aqueous NH Cl, water, and brine, and dried over MgSO .
Removal of the solvent and purification on alumina (as
described above) gave the desired product (342 mg, 59%). Mp:
(
p
1
115 °C (from ethanol). H NMR δ: 0.84-1.80 (m, 22H), 2.66
p
(dd, J ) 3.3 and 15.4 Hz, 1H), 2.70 (dd, J ) 2.3 and 15.4 Hz,
(
p
1H), 3.73 (m, 1H), 3.97 (d, 5H), 4.22 (m, 1H), 4.55 (m, 1H),
1
3
7
.17-7.26 (m, 5H), 7.38 (m, 3H), 7.54-7.58 (m, 2H). C NMR
δ: 21.3 (dd, J ) 9.9 and 19.0 Hz), 26.4, 26.6, 27.1, 27.3 (d, J
9.1 Hz), 27.3 (d, J ) 9.1 Hz), 27.4, 29.4 (d, J ) 7.6 Hz), 29.5
d, J ) 6.8 Hz), 29.6 (d, J ) 12.2 Hz), 30.0 (d, J ) 12.9 Hz),
3.4 (d, J ) 14.4 Hz), 34.1 (d, J ) 14.4 Hz), 68.7, 69.8, 70.6 (d,
(
R
p
p
p
)
(
3
p
2
(
J ) 3.8 Hz), 72.3 (dd, J ) 3.8 and 10.6 Hz), 75.5 (dd, J ) 3.8
and 6.0 Hz), 93.3 (dd, J ) 18.2 and 25.9 Hz), 127.6, 127.9 (d,
J ) 5.3 Hz), 128.0 (d, J ) 7.6 Hz), 129.0, 132.5 (d, J ) 17.5
Hz), 135.2 (d, J ) 20.5 Hz), 138.1 (d, J ) 9.1 Hz), 139.9 (d, J
2
PCl (2.3 g, 10.5 mmol) was added at -78 °C, the mixture
was allowed to warm to room temperature, and stirring was
continued overnight. After the reaction was quenched with
aqueous NaHCO
with brine, and dried over MgSO
and the residue was purified by chromatography on silica.
Elution with PE/Et O/Et N (12/4/1) afforded (R )-12 as a yellow
3
, the organic layer was separated, washed
)
9.1 Hz). 31P NMR δ: -22.6 (d, J ) 5.1 Hz), -1.0 (d, J ) 5.1
4
. The solvent was evaporated,
+
Hz). MS (140 °C) m/z: 580 (3) [M ], 497 (100), 415 (4).
2
0
HRMS: calcd for C35
H
42FeP
2
580.2112, found 580.2130. [R]
+164.7 (589 nm), +174.3 (578 nm), +218.0 (546 nm) (c )
.43, CHCl ) [lit. for (S
λ
2
3
p
)
0
solid (from 10: 2.39 g, 80%; from 11: 2.42 g, 81% yield).
)-14: [R]20
) -160 (589 nm) (c ) 1.0,
λ
3
p
The spectral data of 10-12 are in accordance with the
7
2
4
CHCl
3
)].
)-1-Dip h en ylp h osp h in o-2-[(d ip h en ylp h osp h in o)-
m eth yl]fer r ocen e [(R )-15]. From (R )-8 or (R )-12: diphen-
ylphosphine (223 mg) as nucleophile. From (R )-8: heating at
0 °C for 4 h. From (R )-12: heating at 100 °C for 40 h.
Chromatography with PE (to remove unreacted phosphine)
followed by PE/Et O (20/1) as eluent gave the product as a
yellow solid [159 mg, 28% yield from (R )-8; 216 mg, 38% yield
)-12]. Mp: 55 °C. H NMR δ: 3.35 (s, 2H), 3.75 (m,
values reported in ref 6.
)-2-Ac e t o x y m e t h y l-1-d ip h e n y lp h o s p h in o fe r r o -
(
R
p
(
R
p
7
,17
p
p
p
cen e [(R
p
)-13].
p
A solution of (R )-8 (561 mg, 1 mmol) or
p
(R
p
)-12 (427 mg, 1 mmol) in acetic anhydride (5 mL) was
8
p
degassed and heated for 3.5 h at 120 °C in the case of 8 or 30
min at 80 °C in the case of 12. After the mixture cooled to
room temperature, the acetic anhydride was removed in vacuo
2
p
(
directly from the Schlenk tube), and the residue was dissolved
in CH Cl , washed with 2 N NaOH, water, and brine, and dried
over MgSO . Removal of the solvent and chromatography on
silica with PE/Et O/Et N (24/4/1) as eluent gave acetate (R )-
3 as a yellow solid [from (R )-8: 332 mg, 75%; from (R )-12:
98 mg, 90% yield]. Mp: 139 °C. H NMR δ: 1.60 (s, 3H), 3.77
1
from (R
p
2
2
1
1
1
7
2
H), 3.96 (s, 5H), 4.07 (m, 1H), 4.14 (m, 1H), 7.17-7.45 (m,
8H), 7.56-7.61 (m, 2H). 13C NMR δ: 28.8 (dd, J ) 10.6 and
6.0 Hz), 69.0, 69.9, 70.7 (d, J ) 3.8 Hz), 71.9 (dd, J ) 3.8 and
.6 H), 75.8 (dd, J ) 3.8 and 6.1 Hz), 90.5 (dd, J ) 16.0 and
5.9 Hz), 127.7, 127.9, 128.0 (d, J ) 6.1 Hz), 128.1 (d, J ) 3.0
4
2
3
p
1
3
(
1
(
2
(
1
1
p
p
1
m, 1H), 4.08 (s, 5H), 4.32 (m, 1H), 4.52 (m, 1H), 4.97 (d, J )
Hz), 128.2 (d, J ) 6.8 Hz), 128.3 (d, J ) 6.8 Hz), 128.8, 129.1,
1.9 Hz, 1H), 5.15 (dd, J ) 2.3 and 11.9 Hz, 1H), 7.15-7.24
1
1
32.2 (d, J ) 17.5 Hz), 132.5 (d, J ) 17.5 Hz), 133.5 (d, J )
9.8 Hz), 135.2 (d, J ) 20.5 Hz), 138.0 (d, J ) 8.4 Hz), 140.0
1
3
m, 5H), 7.37-7.40 (m, 3H), 7.51-7.56 (m, 2H). C NMR δ:
0.4, 61.8 (d, J ) 9.9 Hz), 69.6, 70.0, 72.3 (d, J ) 3.8 Hz), 73.0
(
d, J ) 16.0 Hz), 139.3 (d, J ) 16.0 Hz), 140.0 (d, J ) 9.1 Hz).
d, J ) 3.0 Hz), 77.7 (d, J ) 9.1 Hz), 86.3 (d, J ) 24.3 Hz),
3
1
P NMR δ: -22.5 (d, J ) 8.0 Hz), -14.0 (d, J ) 8.0 Hz). MS
27.8 (d, J ) 5.3 Hz), 127.9 (d, J ) 6.1), 128.2 (d, J ) 8.4 Hz),
29.2, 132.5 (d, J ) 18.2 Hz), 134.9 (d, J ) 21.3 Hz), 137.0 (d,
+
(
(
[
(
140 °C) m/z: 568 (31) [M ], 497 (33), 414 (25), 383 (32), 57
100). HRMS: calcd for C35
H
30FeP
2
568.1173, found 568.1161.
) +177.9 (589 nm), +187.0 (578 nm), +214.3 (546 nm)
c ) 0.44, CHCl ) [lit. for (S ) -178 (589 nm) (c )
)-15: [R]20
3
1
J ) 9.1 Hz), 139.7 (d, J ) 9.9 Hz), 170.6. P NMR δ: -22.1.
MS (110 °C) m/z: 442 (75) [M ], 399 (8), 262 (100). HRMS:
2
0
R]
λ
+
23 2 λ
H O )
FeP 442.0785, found 442.0790. [R]20
3
p
λ
calcd for C25
238.7 (589 nm), +251.0 (578 nm), +303.8 (546 nm) (c ) 0.53).
P r ep a r a tion of Liga n d s 14-16. Gen er a l P r oced u r e. A
solution of 1 mmol of (R )-8 (561 mg) or (R )-12 (427 mg) in
7
1
.0, CHCl
)-1-Bis[3,5-bis(tr iflu or om eth yl)p h en yl]p h osp h in o-
m et h yl-2-d ip h en yl-p h osp h in ofer r ocen e [(R )-16]. From
)-12: bis[3,5-bis(trifluoromethyl)phenyl]phosphine
413 mg) as the nucleophile. From (R )-8: heating at 80 °C
)-12: heating at 100 °C for 40 h. Chroma-
tography with PE (to remove unreacted phosphine) followed
by PE/Et O (30/1) as eluent gave the product as a yellow solid
50 mg, 6% yield from (R )-8; 25 mg, 3% yield from (R )-12].
Mp: 47 °C. H NMR δ: 3.29 (dd, J ) 2.8 and 13.9 Hz, 1H),
3
)].
+
(
R
p
p
p
p
(
(
p p
R )-8 or (R
freshly distilled acetic acid (5 mL) was degassed, and the
appropriate dialkyl- or diarylphosphine (1.2 mmol) was added
by syringe. The resulting mixture was degassed again (careful
exclusion of oxygen is crucial to obtain a good yield of the
product) and reacted at elevated temperature (the course of
the reaction was monitored by TLC). After completion, the
reaction mixture was cooled to room temperature, and acetic
acid was removed in vacuo directly from the Schlenk tube. The
p
for 4 h. From (R
p
2
[
p
p
1
3
(
(
4
.67 (ddd, J ) 2.5, 5.0 and 13.9 Hz, 1H), 3.86 (m, 1H), 3.90
m, 1H), 3.97 (s, 5H), 4.20 (m, 1H), 7.14-7.19 (m, 2H), 7.24
residue was dissolved in CH
NaHCO , water, and brine, and dried over MgSO
of the solvent and purification on alumia led to diphosphines
2
Cl
2
, washed with saturated
m, 3H), 7.39 (m, 3H), 7.55-7.60 (m, 2H), 7.68 (d, J ) 5.8 Hz,
3
4
. Removal
13
H), 7.78 (s, 1H), 7.87 (s, 1H). C NMR δ: 29.3 (dd, J ) 9.9
and 16.7 Hz), 69.6, 70.1, 71.7-71.8 (m, 2C), 76.0 (dd, J ) 2.3
1
4-16.
and 8.4 Hz), 87.7 (dd, J ) 16.0 and 27.4 Hz), 122.9-123.0 (m),
1
23.02 (d, J ) 271.2 Hz), 123.04 (d, J ) 271.2 Hz), 123.4-
2
0
123.5 (m), 128.1 (d, J ) 6.8 Hz), 128.1, 128.2 (d, J ) 7.6 Hz),
129.3, 131.5 (d, J ) 27.0 Hz), 131.8-132.1 (m), 131.9 (d, J )
(
24) The specific rotation of (R
p λ
)-11 given in ref 6 should read: [R]
)
+337.6 (589 nm), 359.0 (578 nm), +457.6 (546 nm) (c ) 0.5, CHCl ).
3

Enantiopure 1,2-Disubstituted Ferrocene Derivatives
J . Org. Chem., Vol. 66, No. 26, 2001 8919
3
1
3.4 Hz), 132.6 (dd, J ) 1.5 and 16.7 Hz), 133.3-133.5 (m),
35.0 (d, J ) 20.5 Hz), 137.4 (d, J ) 7.6 Hz), 139.5 (d, J ) 7.6
Ack n ow led gm en t. This work was kindly supported
by O¨ sterreichische Nationalbank (project 7516). A PhD
grant from Bundesministerium f u¨ r Ausw a¨ rtige Angele-
genheiten (Nord-S u¨ d-Dialog Stipendienprogramm) is
kindly acknowleged by L.X.
Hz), 140.5 (d, J ) 23.6 Hz), 141.1 (d, J ) 23.6 Hz). The quoted
1
3
31
13
19
31
coupling constants refer to C- P and C- F. P NMR δ:
24.6 (d, J ) 20.0 Hz), -12.0 (d, J ) 20.0 Hz). MS (120 °C)
-
+
m/z: 840 (86) [M ], 627 (9), 519 (11), 383 (100). HRMS: calcd
2
0
for C39
H
26FeP
2
F
12 840.0668, found 840.0649. [R]
λ
) +147.7
(589 nm), +153.6 (578 nm), +177.2 (546 nm) (c ) 0.39, CHCl
3
).
J O015949Y