Stereoselective synthesis of chiral, non-racemic 1,2,3-tri- and 1,3-disubstituted ferrocene derivatives

Article abstract of DOI:10.1039/b508761a

Chiral, non-racemic 1,2,3-trisubstituted ferrocene derivatives are accessible from monosubstituted ferrocenes through two sequential ortho-deprotonation reactions; removal of the central substituent gives 1,3-disubstituted ferrocenes. The Royal Society of

Full text of DOI:10.1039/b508761a

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Stereoselective synthesis of chiral, non-racemic 1,2,3-tri- and
1,3-disubstituted ferrocene derivatives
Marianne Steurer, Karin Tiedl, Yaping Wang and Walter Weissensteiner*
Received (in Cambridge, UK) 22nd June 2005, Accepted 9th August 2005
First published as an Advance Article on the web 7th September 2005
DOI: 10.1039/b508761a
therefore tested in three reaction sequences in combination with
Chiral, non-racemic 1,2,3-trisubstituted ferrocene derivatives
are accessible from monosubstituted ferrocenes through two
sequential ortho-deprotonation reactions; removal of the central
substituent gives 1,3-disubstituted ferrocenes.
substituents (R1) 1-dimethylaminoethyl [CH(NMe2)Me], the
ephedrine derivative CH2N(Me)CH(Me)CH(Ph)OMe and the
p-tolylsulfinyl [4-CH3C6H4S(O)] unit.
In the first reaction sequence [R1 5 CH(NMe2)Me and
Rc 5 Br (Scheme 2)] commercially available (R)-N,N-(1-dimethyl-
aminoethyl)ferrocene [Ugi’s amine, (R)-1] was reacted using a
literature procedure10 with s-BuLi and F2BrCCBrF2 to give
(R,Sp)-2 in 88% yield. In order to optimise the subsequent
deprotonation step with respect to temperature and the amount of
base, different conditions were applied to the reaction of (R,Sp)-2
with Li-TMP (TMP 5 2,2,6,6-tetramethyl piperidine) as the base
and ClSiMe3 as the electrophile.
Chiral non-racemic ferrocene derivatives have found broad
application as ligands for homogeneous enantioselective catalysts.1
In this respect, 1,2-disubstituted ferrocenes are mainly used
but 1,19,2-tri- or 1,19,2,29-tetrasubstituted ferrocenes are also
employed. In general, ferrocenes with such substitution patterns
are usually prepared from mono- or 1,19-disubstituted precursors
by stereoselective ortho-metallation reactions.2 Interestingly, appli-
cations of chiral non-racemic 1,3-disubstituted ferrocenes are very
rare and this might be due to the fact that suitable methods for the
synthesis of such derivatives are lacking.3 Only recently, in the
context of ferrocene-based pincer ligands,4 Brown and co-workers
reported a broadly applicable method for the synthesis of achiral
or racemic 1,3-disubstituted ferrocene derivatives, with the key
step of this reaction sequence being a selective meta-lithiation of
ferrocenyl-tolyl sulfide.5 Attempts to carry out this reaction in an
enantioselective manner have not yet been successful and, in
addition, methods for separating the enantiomers of racemic
mixtures are very limited.5,6 For these reasons we became
interested in the development of general and preparatively useful
methods for the synthesis of chiral, non-racemic 1,3-disubstituted
ferrocenes.
The use of these optimised conditions{and dimethylformamide
as the electrophile gave aldehyde (R,Rp)-3 exclusively (82%).
Reduction of this compound with LiAlH4 gave alcohol (R,Rp)-4 in
90% yield and subsequent reaction with 2.5 equivalents of n-BuLi
and H2O resulted in the 1,3-disubstituted ferrocenyl aminoalcohol
(R,Sp)-5 (88%). It is clear that a variety of analogous derivatives of
In our search for suitable methods, we investigated the reaction
sequence depicted in Scheme 1: starting from a suitable mono-
substituted ferrocene derivative (Fc-R1), 1,2,3-trisubstituted inter-
mediates are built up in two steps, both of which involve
ortho-deprotonation reactions. Subsequent removal of the central
substituent (Rc) gives 1,3-disubstituted ferrocenes. R1 can be
chosen from a broad selection of ortho-directing groups1,2 but
the central substituent Rc must be both ortho-directing and
removable. Possible candidates for Rc are the halides (chloride7
and bromide8) as well as sulfinyl and sulfonyl groups.9 In our
opinion bromide was best suited for this purpose and it was
Scheme 2 Synthesis of 1,3-disubstituted ferrocenes; reaction sequence 1.
(a) s-BuLi, Et2O, 0 uC, 4 h; 278 uC, F2BrCCBrF2, THF, rt, 17 h, 88%; (b)
Li-TMP, THF, 278 uC 30 min, 230 uC 3 h; DMF, 0 uC 16 h, 82%; (c)
0 uC, LiAlH4, THF, rt, 16 h, 90%; (d) 278 uC, n-BuLi, 0 uC 30 min, H2O,
88%; (e) HPPh2, CH2Cl2, HBF4, rt 16 h, 67%; (f) BH3?THF, rt 16 h, 85%.
TMP 5 2,2,6,6-tetramethylpiperidine, DMF 5 N,N-dimethylformamide.
Overall yield 1 A 5: 57%.
Scheme 1 General reaction scheme for the synthesis of 1,2,3-tri- and 1,3-
disubstituted ferrocenes.
Universita¨t Wien, Fakulta¨t fu¨r Chemie, Wa¨hringer Straße 38, Wien,
A-1090, Austria. E-mail: walter.weissensteiner@univie.ac.at
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Scheme 3 Synthesis of 1,3-disubstituted ferrocenes; reaction sequence 2.
(a) t-BuLi, pentane, 278 uC 1.5 h, 230 uC 2.5 h; F2BrCCBrF2, THF,
278 uC 30 min, rt 16 h, 87%; (b) Ac2O, 150 uC 3 h, 79%; (c) K2CO3,
MeOH, 45 uC 3.5 h, 96%; (d) 0 uC, t-Bu(Me)2SiCl, imidazole, DMF, rt
17 h, 99%; (e) Li-TMP, THF, 278 uC 30 min, 230 uC 3 h; DMF, 0 uC 1 h,
79%; (f) 0 uC, LiAlH4, THF, rt 16 h, 82%; (g) 278 uC, n-BuLi, 0 uC 30 min,
H2O, 90%. TBDMS 5 t-butyldimethylsilyl. Overall yield 8 A 15: 38 %.
Scheme 4 Synthesis of 1,3-disubstituted ferrocenes; reaction sequence 3.
(a) LDA, THF, 278 uC 3 h; F2BrCCBrF2, THF, 278 uC 30 min, rt 19 h,
85%; (b) NaI (6 equiv), Me3SiCl (12 equiv), CH3CN, rt 18 h, 84%; (c)
Li-TMP, THF, 278 uC 30 min, 230 uC 3 h; DMF, 0 uC 1 h, 74%; (d)
LiAlH4, THF, 0 uC 1.5 h, 83%; (e) 278 uC, n-BuLi, 0 uC 30 min, H2O,
92%. Overall yield 16 A 21: 40%.
(Rp)-21 (92%). As recently reported for its racemate,5 21 can easily
be functionalised and can therefore serve as a valuable starting
material for a variety of chiral, non-racemic 1,3-disubstituted
ferrocene derivatives. This approach should also be applicable to
compound 20 or analogues that are accessible from 18 with
different electrophiles.
3, 4 and 5 can be accessed by either using different electrophiles
in the ortho-deprotonation step of 2 or by functional group
tranformation of 4 and 5 or their analogues. As an example, we
synthesised a potential pincer ligand,4 the aminophosphine (R,Sp)-
6 (67%),11 as well as its bisborane complex (R,Sp)-7 (85%).
The second reaction sequence [R1 5 CH2N(Me)CH(Me)-
CH(Ph)OMe and Rc
5 Br (Scheme 3)] starts from an
In summary we have demonstrated that chiral non-racemic
1-R1,2-Rc,3-R2-trisubstituted ferrocenes can be synthesised in two
steps from monosubstituted ferrocenes Fc-R1 with both steps
involving ortho-deprotonations. Particularly combinations of
stereoselectively ortho-directing groups R1 with bromide as the
central substituent gave products with very high selectivity and in
preparatively useful yields. Since bromide can easily be removed
from 1-R1,2-Br,3-R2-trisubstituted ferrocenes, chiral non-racemic
1-R1,3-R2-disubstituted ferrocenes become accessible via this route.
We assume that our method can be further extended with respect
to both the ortho-directing groups R1 and the electrophiles used in
order to introduce substituent R2. Furthermore, functional group
variations of R1 and R2 as well as of bromide will make easily
available a variety of 1,2,3-tri- and 1,3-disubstituted ferrocenes for
new applications.
O-methylephedrine-substituted ferrocene derivative and allows
the synthesis of exclusively planar chiral, non-racemic 1,3-
disubstituted ferrocenes. Monosubstituted ferrocene derivative
(1R,2S)-8, which is easily accessible from N-ferrocenylmethyl-
N,N,N-trimethylammonium iodide and O-methylephedrine,12 was
reacted with t-BuLi and F2BrCCBrF2 to give (1R,2S,Rp)-9 in 87%
yield and 98% d.e. All attempts to selectively ortho-deprotonate
bromide 9 led to product mixtures and, in an effort to overcome
this problem, the O-methylephedrine unit was replaced by a tert-
butyldimethylsilyl-protected hydroxyl group (Scheme 3, 9 A 12,
75%).13 In this case, the use of the reaction conditions optimised
for 2 enabled the selective transformation of bromide (Rp)-12
into aldehyde (Sp)-13 (79%) which, after reduction with LiAlH4,
gave alcohol (Rp)-14 (82%). Finally, reaction with n-BuLi and H2O
removed the bromide and gave the 1,3-disubstituted ferrocene
derivative (Sp)-15 in 90% yield. In this case it is also expected that
derivatives 14 and 15 (like 4 and 5) can serve as enantiopure
starting materials for a number of related products—including
pincer ligands.
The authors thank Solvias AG for a donation of Ugi’s amine
and the undergraduate students Martin Fritzenwanker, Christian
Kowol, Katrin Prantz, Michael Reithofer and Raffael Schuecker
for their enthusiastic help in synthesising a variety of ferrocene
derivatives.
In the third reaction sequence the use of bromide as the central
substituent was combined with the ortho-directing p-tolylsulfinyl
substituent [R1 5 4-CH3C6H4S(O) and Rc 5 Br (Scheme 4)].
Bromide (R,Sp)-17 was prepared by reacting p-tolyl-ferrocenyl
sulfoxide14 (R)-16 with LDA and F2BrCCBrF2 (85%)15 and the
product was subsequently reduced with sodium iodide and
chlorotrimethylsilane to give sulfide (Sp)-18 (84%). As in the
cases of 2 and 12, ferrocene derivative 18 could be selectively
deprotonated adjacent to the bromide substituent and subsequent
reaction with DMF gave aldehyde (Sp)-19 in 74% yield. Reduction
with LiAlH4 resulted in alcohol (Sp)-20, which on reaction with
n-BuLi led to the desired 1,3-disubstituted ferrocene derivative
Notes and references
{ Typical procedure for the ortho-deprotonation of (R,Sp)-2: The reaction
was carried out under an argon atmosphere using standard vacuum line
and Schlenk techniques. To a cooled (278 uC) degassed solution of (R,Sp)-
2 (500 mg, 1.488 mmol) in THF (5 mL) was added dropwise a solution of
Li-TMP in THF (0.7 M, 4.25 mL, 2.976 mmol). The reaction mixture was
stirred for 30 min at 278 uC followed by 3 h at 230 uC. The reaction
temperature was lowered to 278 uC and dimethylformamide (350 mL,
4.516 mmol) was added. The temperature was raised to 0 uC and stirring
continued for 16 h at this temperature. The reaction was quenched with
saturated aqueous Na2CO3 (15 mL) and diethyl ether was added. The
phases were separated and the aqueous phase was extracted 3 times with
4930 | Chem. Commun., 2005, 4929–4931
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diethyl ether. The combined organic phases were washed with brine, dried
(MgSO4) and the solvents removed under reduced pressure. The residue
was purified by column chromatography on alumina. A mixture of
petroleum ether (boiling range 69–72 uC), ethyl acetate and triethylamine
(30 : 10 : 1) was used as the eluent to give product (R,Rp)-3 as a red oil
(442 mg, 82%) . Selected characterisation data. (R,Rp)-3: dH(400.1 MHz;
CDCl3; CHCl3; ppm) 1.47 (3 H, d, J 6.9, CHCH3), 2.17 (6 H, s, N(CH3)2),
3.87 (1 H, q, J 6.9, CHCH3), 4.25 (5 H, s, Cp9), 4.61 (1 H, d, J 2.8, Cp-H4),
4.90 (1 H, d, J 2.8, Cp-H3), 10.22 (1 H, s, CHO); dC(100.6 MHz; CDCl3;
CDCl3; ppm) 15.81 (CH3), 41.04 (N(CH3)2), 55.65 (CH), 65.63 (Cp-C3),
69.59 (Cp-C4), 72.84 (Cp9), 75.29, 92.94 (2 Cp-Cq), 193.94 (CHO), 1 Cp-Cq
not observed; m/z (EI, 60 uC) 362.9928 (M+, 30%; C15H18BrFeNO requires
362.9923), 321/319 (6), 268 (28), 239 (54), 212 (16); [a]l 20 2720 (589 nm),
2806 (578), 21334 (546) (c 0.128 in CHCl3). (R,Sp)-5: yellow powder; mp
1212123 uC; dH(400.1 MHz; CDCl3; CHCl3; ppm) 1.42 (3 H, d, J 6.9,
CHCH3), 1.71 (1 H, br s, OH), 2.09 (6 H, s, N(CH3)2), 3.57 (1 H, q, J 6.9,
CHCH3), 4.12 (1 H, m, Cp-H4), 4.12 (5 H, s, Cp9), 4.21 (1 H, m, Cp-H5),
4.25 (1 H, t, J 1.4, Cp-H2), 4.33 (2 H, s, CH2OH); dC(100.6 MHz; CDCl3;
CDCl3; ppm) 15.55 (CHCH3), 40.62 (N(CH3)2), 58.54 (CHCH3), 60.88
(CH2OH), 66.96, 66.99 (Cp-C4, Cp-C5), 69.00 (Cp9), 69.12 (Cp-C2), 87.75,
87.89 (2 Cp-Cq); m/z (EI, 70 uC) 287.0980 (M+, 81%; C15H21FeNO requires
1 P. Barbaro, C. Bianchini, G. Giambastiani and S. L. Parisel, Coord.
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4 For achiral ferrocene-based pincer ligands see: A. A. Koridze,
S. A. Kuklin, A. M. Sheloumov, F. D. Dolgushin, V. Y. Lagunova,
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20
287.0973), 272 (25), 243 (90), 225 (27), 134 (100). [a]l 21.2 (589 nm),
21.6 (578), 27.9 (546) (c 0.674 in CHCl3). (Sp)-15: yellow powder; mp 55–
2
59 uC; dH(400.1 MHz; CDCl3; CHCl3; ppm) 0.08 [6 H, s,
7 D. W. Slocum, R. L. Marchal and W. E. Jones, Chem.Commun., 1974,
967.
Si(CH3)2C(CH3)3], 0.93 [9 H, s, Si(CH3)2C(CH3)3], 1.49 (1 H, t, J 5.9,
OH), 4.15 (5 H, s, Cp9), 4.19 (1 H, dd, J 2.0 and 1.3, Cp-H4), 4.22 (1 H, dd,
J 2.0 and 1.3, Cp-H5), 4.29 (2 H, d, J 5.9, CH2OH), 4.30 (1 H, t, J 1.3, Cp-
H2), 4.41 (2 H, s, CH2OTBDMS); dC(100.6 MHz; CDCl3; CDCl3; ppm)
25.16 (2C Si(CH3)2C(CH3)3], 18.37 [Cq, Si(CH3)2C(CH3)3], 25.97 [3 C
Si(CH3)2C(CH3)3], 60.75 (CH2OH), 61.16 (CH2OTBDMS), 67.52 (Cp-C4),
67.73 (Cp-C2), 68.03 (Cp-C5), 68.82 (Cp9), 88.43, 88.46 (2 Cp-Cq); m/z (EI,
80 uC) 360.1197 (M+, 100%; C18H28FeO2Si requires 360.1208), 285 (3), 229
(19), 195 (20), 91 (49), 75 (28). [a]l20 26.9 (589 nm), 26.5 (578), 29.1 (546)
(c 0.583 in CHCl3). (Rp)-21: yellow powder; mp 62–68 uC; dH(400.1 MHz;
CDCl3; CHCl3; ppm) 1.57 (1 H, t, J 5.8, OH), 2.27 (3 H, s, CH3C6H4), 4.27
(5 H, s, Cp9), 4.34 (2 H, d, J 5.8, CH2OH), 4.39 (1 H, dd, J 2.4 and 1.5, Cp-
H4), 4.41 (1 H, dd, J 2.4 and 1.5, Cp-H5), 4.48 (1 H, t, J 1.5, Cp-H2), 6.98–
7.02 (2 H, m, C6H4-Hortho), 7.02–7.06 (2 H, m, C6H4-Hmeta); dC(100.6 MHz;
CDCl3; CDCl3; ppm) 20.88 (CH3C6H4), 60.51 (CH2), 69.44 (Cp-C4), 69.99
(Cp9), 74.26 (Cp-C2), 74.83 (Cp-C5), 77.36, 90.05 (2 C, Cp-Cq), 126.94 (2
C,C6H4-Cmeta), 129.43 (2 C, C6H4-Cortho), 135.19, 136.36 (2 C, C6H4-Cq);
m/z (EI, 100 uC) 338.0424 (M+, 100%; C18H18FeOS requires 338.0428), 200
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(85), 185 (37), 167 (15), 138 (11), 121 (19); [a]l 243.3 (589 nm), 244.1
(578), 243.7 (546) (c 0.513 in CHCl3).
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 4929–4931 | 4931