Aminosubstituted tert-butylsulfinylferrocenes as a new family of chiral ligands: Asymmetric addition of diethylzinc to aldehydes

Article abstract of DOI:10.1039/b105962a

A ready access to a new family of planar chiral ferrocenes, the (R_Fc,R_S)-2-amino substituted 1-tert-butylsulfinylferro-cenes, is described; in the case of the sulfonamide series enantioselectivities of up to 96% were obtained in the

Full text of DOI:10.1039/b105962a

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Aminosubstituted tert-butylsulfinylferrocenes as a new family of chiral
ligands: asymmetric addition of diethylzinc to aldehydes
Julián Priego, Olga García Mancheño, Silvia Cabrera and Juan Carlos Carretero*
Departamento de Química Orgánica, Facultad de Ciencias, Universidad Autónoma de Madrid 28049.
Madrid, Spain. E-mail: juancarlos.carretero@uam.es; Fax: 34 91 3973966; Tel: 34 91 3973925
Received (in Cambridge, UK) 5th July 2001, Accepted 3rd September 2001
First published as an Advance Article on the web 12th September 2001
A ready access to a new family of planar chiral ferrocenes,
the (RFc,RS)-2-amino substituted 1-tert-butylsulfinylferro-
cenes, is described; in the case of the sulfonamide series
enantioselectivities of up to 96% were obtained in the
addition of Et2Zn to aromatic aldehydes.
During the last two decades the sulfinyl group has been
extensively used as a chiral auxiliary in emblematic C–C bond
forming reactions, such as Diels–Alder cycloadditions and
Scheme 1 Synthesis of 2-amino(sulfinyl)ferrocene 2a.
nucleophile additions,1 and more recently has started to be
applied in transition metal-catalyzed reactions.2 However,
despite the huge interest currently devoted to the development
of highly efficient chiral ligands for asymmetric catalysis,
usually involving P,P- P,N- or N,N-bidentate metal-coordinat-
ing ligands,3 few examples of chiral ligands based on sulfoxides
have been reported,4 most of them being tested only in
asymmetric palladium-catalyzed allylic substitutions. Among
the wide structural diversity of chiral frameworks commonly
used in asymmetric catalysis, the planar chirality of 1,2-di-
substituted ferrocene derivatives has received a great attention.5
Within this context, we describe herein the synthesis of
enantiopure (RFc,RS)-2-amino substituted tert-butylsulfinylfer-
rocenes as a new family of sterically and electronically
adjustable chiral ligands and their application to the asymmetric
addition of Et2Zn to aromatic aldehydes.6
The synthesis of tert-butyl ferrocenyl sulfoxide (1) in high
optical purity had been previously described by enantioselective
oxidation of the corresponding thioether and by sulfinylation of
ferrocenyllithium with an enantiopure tert-butylsulfinate.7 Al-
ternatively, we have prepared (R)-1 by direct sulfinylation of
ferrocenyllithium (formed in situ by deprotonation of ferrocene
with t-BuLi in THF) with (R)-S-tert-butyl 1,1-dimethylethane-
thiosulfinate.8 This one-step procedure is experimentally quite
simple (THF, 0 °C), affording ferrocene (R)-1 in 40% yield after
flash chromatography (58% of starting ferrocene is recovered).
The recrystallization from hexane–ether (1+1) yielded (R)-1 in
very high optical purity9 (ee = 99%, HPLC, Daicel Chiralcel
OD column).
compounds such as substituted amines (2b), amides (2c–f) and
sulfonamides (2g–l) following straightforward reactions of
amine derivatization (Scheme 2).
With this family of ligands in hand, we examined their
effectiveness as chiral catalysts in one of the most prototypical
reactions in chiral ligand screening: the addition of diethylzinc
to benzaldehyde.6 The reactions were performed under typical
conditions: 5 mol% of ligand 2, excess of diethylzinc (200
mol%) in toluene at rt (Table 1). In most cases the complete
disappearance of benzaldehyde was observed after 1–4 days,
affording in acceptable to good yields the alcohol 3 with
enantioselectivities very dependent on the substitution at the
nitrogen atom. While a low enantiocontrol occurred using the
amine (entries 1 and 2) and amide ligands (entries 3–6), a more
interesting outcome was observed in the case of the sulfonamide
ligands (entries 7–14), which provided (R)-3 in 42 to 88% ee’s.
The best ligands were found to be the p-tolylsulfonamide 2h
(80% ee, entry 8) and the p-methoxyphenylsulfonamide 2i
(82% ee, entry 10). It is worth noting that in both cases the
According to the previously reported cases of highly
stereoselective ortho C-2 deprotonation of ferrocenyl sulf-
oxides with strong bases,7 the treatment of 1 with n-BuLi (THF,
0 °C) generated selectively the C-2 lithiated tert-butylsulfi-
nylferrocene.10 This solution was treated with tosyl azide to
give the intermediate ferrocenyl azide, followed by in situ
reduction with NaBH4, which afforded the amino(sulfinyl)fer-
rocene 2a (64% yield) in very high optical purity (ee > 98%,
HPLC, Chiralpak AS column) (Scheme 1).
In the search of efficient chiral ligands for enantioselective
synthesis, the ready access to a wide diversity of substrates with
adjustable steric and electronic properties around the metal-
coordinating atoms is a crucial point. In this context, having
developed a practical two-step procedure for the preparation of
enantiopure 2a in gram quantities from ferrocene, the amino
group was readily transformed into a variety of nitrogen
† Electronic supplementary information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/cc/b1/b105962a/
Scheme 2 Synthesis of ligands 2 bearing subtituted amines, amides and
sulfonamides.
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Chem. Commun., 2001, 2026–2027
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b105962a

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Table 1 Diethylzinc addition to benzaldehyde catalyzed by the ligands 2
Table 2 Diethylzinc addition to aromatic aldehydes catalyzed by the ligands
2h and 2i
3
Product,
(R) conf. Ee (%)b Yield (%)c
Entrya
Ar
Ligand
Entrya
Ligand
Ee (%)b
Conf.
Yield (%)c
1
2
3
4
5
6
7
8
p-NO2C6H4
p-NO2C6H4
p-MeOC6H4
p-MeOC6H4
p-MeC6H4
p-MeC6H4
p-CO2MeC6H4 2h
p-CO2MeC6H4 2i
2-Naphthyl
2-Naphthyl
m-FC6H4
2h
2i
2h
2i
2h
2i
4
4
5
5
6
6
7
7
8
8
9
9
28
26
73e
75e
65e
61e
86
72
71
78
73
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2h
2i
2i
2j
2k
2l
2m
2n
28
6
60
6
14
8
74
80
88
82
86
58
48
42
82
74
S
93
59
76
67e
70
74
90
79
80e
82
76e
62e
68
51
85
81
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
66d
58d
64d
66d
88
96
82
92
80
9
2h
2i
2h
2i
9d
10
11d
12
13
14
15
16
a
10
11
12
a
79
76
74
m-FC6H4
72
Reaction conditions: Et2Zn (200 mol%), ligand (5 mol%), toluene, rt, 1–4
b
c
days. Determined by HPLC (Daicel Chiralpak AD). In pure alcohol
after flash chromatography. d Determined by HPLC (Daicel Chiralcel OD).
e
Conversion yield.
Reaction conditions: Et2Zn (200 mol%), ligand (5 mol%), toluene, rt, 1–4
days. b Determined by HPLC (Daicel Chiralcel OD). c In pure alcohol after
flash chromatography. d Reaction run at 220 °C. e Conversion yield.
Notes and references
1 Recent review: J. L. Garcia Ruano and B. Cid de la Plata, Top. Curr.
Chem., 1999, 204, 1.
2 Very recent references: K. Hiroi, Y. Suzuki, F. Kato and Y. Kyo,
Tetrahedron: Asymmetry, 2001, 12, 37; N. Díaz Buezo, O. García
Mancheño and J. C. Carretero, Org. Lett., 2000, 2, 1451; K. Hiroi and
A. Yamada, Tetrahedron: Asymmetry, 2000, 11, 1835.
3 Catalytic Asymmetric Synthesis, ed. I. Ojima, 2nd edn., VCH, New
York, 2000; Comprehensive Asymmetric Catalysis, eds. E. N. Jacobsen,
A. Pfaltz and H. Yamamoto, Springer, Berlin, 1999.
4 Recent references: K. Hiroi, Y. Suzuki, I. Abe and R. Kawagishi,
Tetrahedron, 2000, 56, 4701; D. G. I. Petra, P. C. J. Kamer, A. L. Spek,
H. E. Schoemaker and P. W. N. M. van Leeuwen, J. Org. Chem., 2000,
65, 3010; K. Hiroi, Y. Suzuki and R. Kawagishi, Tetrahedron Lett.,
1999, 40, 715; K. Hiroi, Y. Suzuki, I. Abe, Y. Hasegawa and K. Suzuki,
Tetrahedron: Asymmetry, 1998, 9, 3797; See also: M. C. Carreño, J. L.
García Ruano, M. C. Maestro and L. M. Martín Cabrejas, Tetrahedron:
Asymmetry, 1993, 4, 727.
5 Ferrocenes: Homogeneous Catalysis. Organic Synthesis. Material
Science, eds. T. Hayashi and A. Togni, VCH, Weinheim, Germany,
1995. Recent reviews, see: C. J. Richards and A. J. Locke, Tetrahedron:
Asymmetry, 1998, 9, 2377; A. Togni, Angew. Chem., Int. Ed. Engl.,
1996, 35, 1475.
6 Recent review: L. Pu and H.-B. Yu, Chem. Rev., 2001, 101, 757.
7 N. M. Lagneau, Y. Chen, P. M. Robben, H.-S. Sin, K. Takasu, J.-S.
Chen, P. D. Robinson and D. H. Hua, Tetrahedron, 1998, 54, 7301; P.
Diter, O. Samuel, S. Taudien and H. B. Kagan, Tetrahedron:
Asymmetry, 1994, 5, 549; F. Rebière, O. Riant, L. Ricard and H. B.
Kagan, Angew. Chem., Int. Ed. Engl., 1993, 32, 568.
enantioselectivity of the process was enhanced significantly by
performing the reaction at 220 °C instead of rt (entries 9 and 11,
88 and 86% ee, respectively).
In order to clarify whether the enantiocontrol exerted by the
chiral ligand was predominantly due to the planar chirality of
the ferrocenyl moiety or to the stereogenic sulfur atom, the
optimal sulfoxides 2h and 2i were reduced to the corresponding
thioethers 2m and 2n by reaction with NaI–(CF3CO)2O in
acetone (89 and 74% yields, respectively). Interestingly, the
addition of Et2Zn to benzaldehyde at rt in the presence of both
2m and 2n (entries 15 and 16) occurred with an enantioselectiv-
ity very similar to that observed for the corresponding
sulfoxides 2h and 2i (entries 8 and 10), showing that the planar
chirality of ferrocene is the main structural factor involved in
the asymmetric induction.11
Finally, to explore the substrate generality of this enantiose-
lective process, the ligands 2h and 2i were tested in the addition
of Et2Zn to differently substituted aromatic aldehydes under the
same experimental conditions. As depicted in Table 2, both
ligands 2h and 2i behaved similarly, affording in all cases the
alcohol of (R) configuration as the main enantiomer12 in good
chemical yields. With the exception of the case of p-
nitrobenzaldehyde (entries 1 and 2), moderate to high enantio-
selectivities were observed with the rest of aldehydes (ee’s from
58 to 96%, entries 3–12).
8 D. A. Cogan, G. Liu, K. Kim, B. J. Backes and J. A. Ellman, J. Am.
Chem. Soc., 1998, 120, 8011.
In summary, a novel family of enantiopure ferrocene ligands,
the (RFc,RS)-2-amino substituted 1-tert-butylsulfinylferrocenes
2, has been readily synthesized from ferrocene. Using sulfona-
mide ligands (especially 2h and 2i) moderate to high asym-
metric inductions were obtained in the addition of Et2Zn to
aromatic aldehydes. The application of this new type of chiral
ferrocene ligand to other asymmetric C–C bond forming
reactions is under active investigation.
This work was supported by the Ministerio de Ciencia y
Tecnología (project BQU2000-0266). J. P. and O. G. M. also
thank the Ministerio de Educación y Cultura for their pre-
doctoral fellowships.
9 The sulfinylation of ferrocenyllithium occurred with virtually complete
inversion of configuration at sulfur. For instance, from (R)-tert-butyl
1,1-dimethylethanesulfinate of ee = 80% (R)-1 was obtained with the
same optical purity (ee = 80%).
10 This high diastereoselectivity is due to the strong steric preference of the
tert-butyl group to be in the anti orientation with regard to the iron atom,
see ref. 7.
11 C. Bolm and K. Muñiz, Chem. Eur. J., 2000, 6, 2309; C. Bolm, K.
Muñiz, A. Seger, G. Raabe and K. Günther, J. Org. Chem., 1998, 63,
7860.
12 All obtained alcohols (R)-4–9 are dextrorotatory. See, for instance: W.-
M. Dai, H.-J. Zhu and X.-J. Hao, Tetrahedron: Asymmetry, 2000, 11,
2315.
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