A straightforward asymmetric synthesis of 1,2-disubstituted ferrocenylalkyl amines with the unusual (SFc,S) configuration

Article abstract of DOI:10.1039/b710109k

A useful synthesis of rare 1,2-disubstituted ferrocenylalkyl amines with (S_Fc,S) configuration has been achieved in a sequential one-pot methodology from (S)-p-tolylsulfinylferrocene. The Royal Society of Chemistry.

Full text of DOI:10.1039/b710109k

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A straightforward asymmetric synthesis of 1,2-disubstituted
ferrocenylalkyl amines with the unusual (SFc,S) configuration{
Guillaume Grach,a Jean-Franc¸ois Lohier,a Jana Sopkova-de Oliveira Santos,b Vincent Reboul*a and
Patrick Metzner*a
Received (in Bloomington, IN, USA) 3rd July 2007, Accepted 19th September 2007
First published as an Advance Article on the web 2nd October 2007
DOI: 10.1039/b710109k
1-ferrocenylalkyl- (different from methyl) and 1-ferrocenylaryl-
amines derivatives7 were not very common due to the lack of
efficient method8 for their preparation whereas they were
demonstrated to be more effective, as chiral ligands, than the
parent methyl-substituted derivatives for some catalytic asym-
metric reactions.9 Only one example to date illustrated this purpose
with the synthesis of (R,RFc)-Taniaphos10 and its use as efficient
ligand for asymmetric reactions.11
A useful synthesis of rare 1,2-disubstituted ferrocenylalkyl
amines with (SFc,S) configuration has been achieved in a
sequential one-pot methodology from (S)-p-tolylsulfinylferro-
cene.
Due to their properties, particularly those regarding rigidity, ease
of derivatization and planar chirality, ferrocenyl compounds
have been widely used in asymmetric catalysis.1 Planar chirality
of 1,2-disubstituted ferrocenes is often a decisive factor for exerting
control over the absolute configuration and enantiomeric excess.2
Many of these ferrocenyl ligands were prepared by diastereoselec-
tive ortho-lithiation of N,N-dimethyl-1-ferrocenylethylamine (Ugi’s
amine), followed by introduction of an appropriate electrophile.3
Consequently, the resulting ferrocenes have both planar and
central chirality with (SFc,R) or (RFc,S) configurations (Scheme 1).
For the diversity of ligand configuration, there is a need to develop
a convenient method for the synthesis of the other diastereoisomer
of such compounds.
Recently, we have developed the diastereoselective addition of
lithiated tert-butylsulfinylferrocene 1a to imines leading to
enantiopure 1-ferrocenylalkyl amines 3a (with various alkyl and
aryl groups) having (SS,SFc,S) configurations (Scheme 2).12
Scheme 2
In this context, we argued that the rare 1,2-disubstituted
ferrocenes 4 with (SFc,S) configurations (Fig. 1) would be
accessible from 3 if the sulfoxide can be replaced by an electrophile.
We now wish to report our preliminary results on the synthesis of
3 and their transformation to 4.
Scheme 1
Indeed, only few reports described the synthesis of ligands with
(RFc,R) or (SFc,S) configurations. The main approach involved the
introduction of a trimethylsilyl group in the ortho-position of Ugi’s
amine, further difficult metallation on the other ortho-position
followed by electrophile introduction and then desilylation by
treatment with fluoride anion.4 Recently, a second process was
described from (SFc)-a-substituted ferrocenecarbaldehydes5 in
three steps.6
Fig. 1
Moreover, the use of Ugi’s amine as starting material does not
allow any variation of substituent of the asymmetric carbon:
always a methyl group. On the other hand, the synthesis
When (S)-tert-butylsulfinylferrocene 1a was submitted to ortho-
metallation followed by alkyl or aryl imine addition (Table 1),
aminosulfoxides 3a were obtained with complete diastereocontrol
when Boc groups were used as electron withdrawing groups on the
nitrogen atom (entry 7). In most cases, the dr decreased by the use
of N-tosyl group (entries 1, 3 and 5). However, we were pleased to
find that using sulfoxide 1b13 (R1 = p-tolyl) and LDA as a base
(1.2 eq., 278 uC, 30 min), complete asymmetric induction was
obtained with both N-Boc14 and N-Ts series (entries 2, 4 and 8).15
The expected (SS,SFc,S) configuration was confirmed by X-ray
analysis of 3bb (Fig. 2).16{ An unusual weak hydrogen bonding
aLaboratoire de Chimie Mole´culaire et Thio-organique, ENSICAEN,
Universite´ de Caen Basse-Normandie, CNRS, 6 boulevard du Mare´chal
Juin, 14050, Caen, France. E-mail: vincent.reboul@ensicaen.fr;
Fax: +(33) 231 452 877; Tel: +(33) 231 452 884
bDe´partement de radiocristallographie, Centre d’Etudes et de Recherche
sur le Me´dicament de Normandie-Universite´ de Caen Basse-Normandie,
14032, Caen, France
{ Electronic supplementary information (ESI) available: Experimental
procedures and characterization for all new compounds described. See
DOI: 10.1039/b710109k
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Table 1 Diastereoselective ortho-lithiation followed by aldimine addition
Entry
Sulfoxide
Base
Imine (R2, Ts) or sulfone (R2, Boc)
Product
Isolated yield (%)
dra
1
2
3
4
5
6
7
8
a
1a
1b
1a
1b
1a
1b
1a
1b
n-BuLi
LDA
n-BuLi
LDA
n-BuLi
LDA
n-BuLi
LDA
i-Pr, Ts
i-Pr, Ts
Ph, Ts
Ph, Ts
t-Bu, Ts
t-Bu, Ts
i-Pr, Boc
i-Pr, Boc
b
3aa
3ba
3ab
3bb
3ac
3bc
3ad
3bd
55
66
65
74
90 : 10
.98 : 2
75 : 25
.98 : 2
64 : 36
84 : 16
.98 : 2
.98 : 2
54
82
76b
58a,b
Determined by 1H NMR on the crude product. Based on sulfone.
Table 2 Preliminary scope of the sequential one-pot reaction
Isolated
Compound yield (%)
Entry EX
E
Fig. 2 X-Ray crystal structure of 3bb (50% thermal ellipsoids).
1
2
3
4
5
6
7
8
9
a
H2O
H
4a
4b
4c
4d
4e
4f
49
41
52
51
42
46
43
44
41a
Hydrogen atoms are omitted for clarity except for C*H and NH.
Ph2PCl
PhSSPh
TMSCl
Bu3SnCl
I2
PPh2
SPh
TMS
SnBu3
I
…
between the C*H and the sulfinyl oxygen (S(O) C*H: 2.476 A;
˚
C–H–O angle: 130.3u) was observed.
As a test reaction we next studied the displacement reaction of
the p-tolylsulfinyl group with t-BuLi (278 uC, 15 min),17 using first
3ba (bearing an N-tosyl group18) in order to synthesize 4a, an
enantiopure analog of Ugi’s amine (R2 = i-Pr, E = H).19 Using 2.1
eq. of base then water as electrophile, 4a was isolated with 85%
yield and er 99 : 1 (enantioselective HPLC). As 3ba was obtained
as a single diastereoisomer, we envisioned to perform the whole
sequence in one-pot reaction starting form sulfoxide 1b (scheme in
Table 2). Thus, 4a was obtained in 49% yield20 and er 99 : 1, that
confirmed no epimerization occurred during all this process.21
We explored the scope of the sequential one-pot reaction firstly
with chlorodiphenylphosphine as electrophile (Table 2, entry 2). In
addition to the expected 4b (Fig. 3),22{ we were surprised to isolate
t-BuS(O)St-Bu (R) S(O)t-Bu (R) 4g
PhCOPh
PhCHO
C(OH)Ph2
CH(OH)Ph
4h
4i
53 : 47 inseparable mixture of diastereoisomers.
non phosphinylated 4a in respectively a 68 : 32 ratio.23
A
protonation reaction of a dilithiated species by diisopropylamine
(generated in the first step) could explain this result. To overcome
this problem, we decided to carry out the synthesis of 4b from
isolated 3ba (Scheme 3). Surprisingly, exposure of 3ba to t-BuLi
followed by PPh2Cl allowed the formation of phosphinamidite 5
as a major product and the expected phosphine 4b, respectively in
a 72 : 28 ratio with 90% yield. Monosubstituted ferrocene 4a or
hybrid phosphine-phosphinamidite24 compound were not detected
in the crude product. The amount of 5 can be reduced by using
NaH, which deprotonates 3ba but which does not displace the
sulfoxide moiety.25 Thus an excess of this base (3 eq.) followed
(after completed gas evolution) by 1.1 eq. of t-BuLi, led to 5 and 4b
in 29 : 71 ratio. A similar result was obtained during the one-pot
sequence (51 : 49 ratio).
Fig. 3 X-Ray crystal structure of 4b (50% thermal ellipsoids). Hydrogen
atoms are omitted for clarity except for C*H and NH.
Using conditions established for 4a, a variety of electrophiles
were next examined. A summary of the results is reported in
Table 2. Our expeditious methodology was shown to be
Scheme 3
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J. Wang, C. Bai and Z. Zheng, Tetrahedron: Asymmetry, 2002, 13,
1687–1693; (d) S. Yasuike, C. C. Kofink, R. J. Kloetzing,
N. Gommermann, K. Tappe, A. Gavryushin and P. Knochel,
Tetrahedron: Asymmetry, 2005, 16, 3385–3393; (e) T. Fukuda,
A. Takehara, N. Haniu and M. Iwao, Tetrahedron: Asymmetry, 2000,
11, 4083–4091; (f) G. Glorian, L. Maciejewski, J. Brocard and
F. Agbossou, Tetrahedron: Asymmetry, 1997, 8, 355–358; (g) X. Hu,
H. Chen, X. Hu, H. Dai, C. Bai, J. Wang and Z. Zheng, Tetrahedron
Lett., 2002, 43, 9179–9182; (h) H. K. Cotton, J. Norinder and
J.-E. Baeckvall, Tetrahedron, 2006, 62, 5632–5640.
compatible and efficient with various functionalities: sulfide, silane,
stannane, halogen, sulfoxide and alcohols (41–52% yield for four
steps).26
In conclusion, we have established a rapid and convergent
methodology for the synthesis of a range of enantiopure ferrocenyl
derivatives with the unusual (SFc,S) configurations. The potential
use of these new compounds for the preparation of chiral ligands
for asymmetric catalysis is currently under investigation in our
laboratories. Crucial influence of N–H proton in the ligand could
be particularly studied.27
8 Difficulties of reproducibility of enantioselective CBS-reduction of
ferrocenyl ketones (see ref. 7h) and of lithiation diastereoselectivity have
been encountered (see ref. 7b).
Financial support from the ‘‘PunchOrga’’ Network (Poˆle
Universitaire Normand de Chimie Organique), the ‘‘Re´gion
Haute-Normandie’’, the ‘‘Re´gion Basse-Normandie’’, the
‘‘Ministe`re de la Recherche’’, CNRS (Centre National de la
Recherche Scientifique), and the European Union (FEDER
funding) is acknowledged.
9 A. Ohno, M. Yamane, T. Hayashi, N. Oguni and M. Hayashi,
Tetrahedron: Asymmetry, 1995, 6, 2495–2502.
10 Original (R,SFc)-Taniaphos: (a) T. Ireland, G. Grossheimann, C. Wieser-
Jeunesse and P. Knochel, Angew. Chem., Int. Ed., 1999, 38, 3212–3214;
(b) T. Ireland, K. Tappe, G. Grossheimann and P. Knochel, Chem.–Eur.
J., 2002, 8, 843–852.
11 S.-I. Fukuzawa, M. Yamamoto and S. Kikuchi, J. Org. Chem., 2007,
72, 1514–1517.
12 G. Grach, J. Sopkova-de Oliveira Santos, J.-F. Lohier, L. Mojovic,
N. Ple´, A. Turck, V. Reboul and P. Metzner, J. Org. Chem., 2006, 71,
9572–9579.
13 Sulfoxide 1b was prepared according to: (a) H. K. Cotton, F. F. Huerta
and J.-E. Ba¨ckvall, Eur. J. Org. Chem., 2003, 2756–2763. For recent
review in the use of this sulfinyl ferrocene: (b) B. F. Bonini, M. Fochi
and A. Ricci, Synlett, 2007, 360–373; (c) B. Ferber and H. B. Kagan,
Adv. Synth. Catal., 2007, 349, 493–507.
14 We were not able to separate remaining sulfoxide 1b and adduct 3ba on
silica gel. Thus, the yield was estimated by 1H NMR on the crude
product.
15 Except the particular case of N-tosylimine (R2 = t-Bu). The dr was
however increased (entry 6; 84 : 16 dr) as compared to the use of tert-
butyl sulfoxide 3a (entry 5; 64 : 36 dr).
Notes and references
{ Crystal data for 3bb: C31H29FeNO3S2, M = 583.54, crystal size 0.54 6
0.31 6 0.27 mm, orthorhombic, space group P212121, a = 12.2501(3), b =
3
˚
˚
13.4034(3), c = 16.6923(4) A, V = 2740.76(10) A , T = 296 K, Z = 4, m =
0.736 mm21, 86850 reflections collected, refinement for 8385 reflections and
345 parameters gave GOF = 1.110, R1 = 0.0346 and wR2 = 0.0830,
˚
absolute structure parameter = 0.002(9). Selected bond lengths (A) and
angles (u): C*–CCp1.5117(19), S–O 1.5063(12), S–CCp 1.7573(15), C*–N
1.4707(19); N–C*–CCp 108.75(12); O–S–CCp–CCp 228.6.
Crystal data for 4b: C33H34FeNO2PS, M = 595.51, crystal size 0.53 6
0.09 6 0.03 mm, monoclinic, space group C2c, a = 28.0611(10), b =
3
˚
˚
10.3417(3), c = 24.2234(9) A, V = 5768.7(4) A , T = 100 K, Z = 8, m =
0.682 mm21, 103330 reflections collected, refinement for 8751 reflections
and 488 parameters gave GOF = 1.086, R1 = 0.0812 and wR2 = 0.0981.
16 Single crystals were obtained from a concentrated solution of AcOEt
and by slow diffusion of n-heptane.
17 O. Riant, G. Argouarch, D. Guillaneux, O. Samuel and H. B. Kagan,
J. Org. Chem., 1998, 63, 3511–3514.
˚
Selected bond lengths (A) and angles (u): C*–CCp 1.512(3), CCp–P 1.820(2),
C*–N 1.469(2); P–CCp–CCp–C* 25.01.
CCDC 652839 and 652840. For crystallographic data in CIF or other
electronic format see DOI: 10.1039/b710109k
18 The N-Boc moiety was not chosen due to its poor aptitude to catalyze
asymmetric reaction: N. W. Boaz, J. A. Ponasik, S. E. Large and
S. D. Debenham, Tetrahedron: Asymmetry, 2004, 15, 2151–2154.
19 Asymmetric synthesis of N-Cbz compound has also been described:
P. Laurent, H. Miyaji, S. R. Collinson, I. Prokes, C. J. Moody,
J. H. R. Tucker and A. M. Z. Slawin, Org. Lett., 2002, 4, 4037–4040.
20 As the formation of 3ba was not completed (Table 1, entry 2), the
remaining starting material was transformed into ferrocene by action of
t-BuLi followed by hydrolysis. No other ferrocenic compound has been
isolated.
1 (a) C. J. Richards and A. J. Locke, Tetrahedron: Asymmetry, 1998, 9,
2377–2407; (b) R. C. J. Atkinson, V. C. Gibson and N. J. Long, Chem.
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G. Giambastiani and S. L. Parisel, Coord. Chem. Rev., 2004, 248,
2131–2150; (d) R. Gomez Arrayas, J. Adrio and J. C. Carretero, Angew.
Chem., Int. Ed., 2006, 45, 7674–7715.
2 L.-X. Dai, T. Tu, S.-L. You, W.-P. Deng and X.-L. Hou, Acc. Chem.
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21 While only one equivalent was theoretically sufficient, the best result was
obtained using 2.2 eq. of t-BuLi.
22 We were able to crystallize only the racemic 4b from ethanol.
Consequently, only the (S,SFc) enantiomer was represented.
23 4a, 4b and ferrocene were easily separated by column chromatography.
24 Due to steric hindrance, the synthesis of this compound from 4b using
PPh2Cl seems to be very difficult: N. W. Boaz, J. A. Ponasik and
S. E. Large, Tetrahedron: Asymmetry, 2005, 16, 2063–2066.
25 An analogous case was reported for the deprotonation of fluorous
alcohols by NaH: V. Albrow, A. J. Blake, A. Chapron, C. Wilson and
S. Woodward, Inorg. Chim. Acta, 2006, 359, 1731–1742.
26 That is to say an average of 80–85% yield by step. For entries 2–9, 4a
and ferrocene were obtained as byproducts.
4 (a) T. Hayashi, T. Mise, M. Fukushima, M. Kagotani, N. Nagashima,
Y. Hamada, A. Matsumoto, S. Kawakami, M. Konishi, K. Yamamoto
and M. Kumada, Bull. Chem. Soc. Jpn., 1980, 53, 1138–1151; (b) X. Hu,
H. Chen, H. Dai, X. Hu and Z. Zheng, Tetrahedron: Asymmetry, 2003,
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Asymmetry, 2003, 14, 3415–3421.
5 Synthesized in four steps from ferrocenecarbaldehyde: O. Riant,
O. Samuel, T. Flessner, S. Taudien and H. B. Kagan, J. Org. Chem.,
1997, 62, 6733–6745.
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Asymmetry, 2006, 17, 1161–1164.
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G.-Y. Chen, Y.-G. Zhou and Y.-X. Li, J. Am. Chem. Soc., 2007, 129,
750–751.
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2000, 41, 9233–9237; (b) K. Tappe and P. Knochel, Tetrahedron:
Asymmetry, 2004, 15, 91–102; (c) X. Hu, H. Dai, X. Hu, H. Chen,
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Chem. Commun., 2007, 4875–4877 | 4877