Diastereoselective addition of enantiopure lithium tert- butylsulfinylferrocene to imines

Article abstract of DOI:10.1021/jo061360t

(S)-terf-Butylsulfinylferrocene was submitted to ortho-metalation, and the corresponding lithium derivative was trapped by alkyl or aryl imines bearing various electron-withdrawing groups on the nitrogen atom (Ts, Dpp, Boc). New aminosulfoxides were obtai

Full text of DOI:10.1021/jo061360t

Diastereoselective Addition of Enantiopure Lithium
tert-Butylsulfinylferrocene to Imines
Guillaume Grach,† Jana Sopkova-de Oliveira Santos,‡ Jean-Franc¸ois Lohier,†
Ljubica Mojovic,§ Nelly Ple´,§ Alain Turck,§ Vincent Reboul,*,† and Patrick Metzner*,†
Laboratoire de Chimie Mole´culaire et Thio-organique, UMR CNRS 6507, ENSICAEN, UniVersite´ de Caen,
14050 Caen, France, Centre d’Etudes et de Recherche sur le Me´dicament de Normandie, UniVersite´ de
Caen, 14032 Caen, France, and Laboratoire de Chimie Organique Fine et He´te´rocyclique, UMR CNRS
6014, IRCOF, INSA, B.P. 08, 76131 Mont Saint Aignan, France
Vincent.reboul@ensicaen.fr
ReceiVed June 30, 2006
(S)-tert-Butylsulfinylferrocene was submitted to ortho-metalation, and the corresponding lithium derivative
was trapped by alkyl or aryl imines bearing various electron-withdrawing groups on the nitrogen atom
(Ts, Dpp, Boc). New aminosulfoxides were obtained with complete diastereocontrol when Dpp or Boc
groups were used. The absolute configuration (SS,SFc,S) has been determined by single-crystal X-ray
analysis and chemical correlation. An unusual pseudocyclic boatlike transition state has been proposed
to explain the stereochemical course of this reaction.
Introduction
easy preparation of the starting material (two enantiomers
available in only one step from ferrocene). Moreover, the
sulfoxide moiety may be transformed into other functional
groups or may be removed.6 The resulting lithium sulfinylfer-
rocene 5 derivatives were trapped with electrophiles leading to
1,2-substitution (Scheme 1).7
Only a few prochiral electrophiles have been used with 5,
probably as the result of the very low asymmetric induction
observed.8,9 For example, in the arylsulfinyl series, Knochel
described the use of 2-(diphenylphosphine)-benzaldehyde with
the lithio derivative 5 (R ) p-Tol) leading to a 55:45 mixture
of diastereoisomers, which were not easily separable. No
Since the first diastereoselective ortho-lithiation of N,N-
dimethyl-1-ferrocenylethylamine (1) was reported1 by Ugi in
1970, alternative ortho-directing groups2 have been used with
success and allowed the preparation of enantiopure 1,2-
disubstituted ferrocene derivatives with planar and central
chirality.3 Among them, the stereogenic sulfinyl group has
emerged recently with the methodology developed by Kagan4
and Hua,5 using enantiopure p-tolylsulfinylferrocene (3) and tert-
butylsulfinylferrocene (4). This interest was largely due to the
* To whom correspondence should be addressed.
† Laboratoire de Chimie Mole´culaire et Thio-organique.
‡ Centre d’Etudes et de Recherche sur le Me´dicament de Normandie.
§ Laboratoire de Chimie Organique Fine et He´te´rocyclique.
(1) Marquading, D.; Klusacek, H.; Gokel, G. W.; Hoffmann, P.; Ugi, I.
K. J. Am. Chem. Soc. 1970, 92, 5389-5393.
(4) (a) Riant, O.; Argouarch, G.; Guillaneux, D.; Samuel, O.; Kagan, H.
B. J. Org. Chem. 1998, 63, 3511-3514. (b) Rebie`re, F.; Riant, O.; Ricard,
L.; Kagan, H. B. Angew. Chem., Int. Ed. Engl. 1993, 32, 568-570.
(5) (a) Lagneau, N. M.; Yi, C.; Robben, P. M.; Sin, H.-S.; Takasu, K.;
Chen, J.-S.; Robinson, P. D.; Hua, D. H. Tetrahedron 1998, 54, 7301-
7334. (b) Hua, D. H.; Lagneau, N. M.; Chen, Y.; Robben, P. M.; Clapham,
G.; Robinson, P. D. J. Org. Chem. 1996, 61, 4508-4509.
(6) (a) See ref 4a. (b) Pedersen, H. L.; Johannsen, M. Chem. Commun.
1999, 2517-2518. (c) Lotz, M.; Polborn, K.; Knochel, P. Angew. Chem.,
Int. Ed. 2002, 41, 4708-4711.
(2) Last example to date: Vinci, D.; Mateus, N.; Wu, X.; Hancock, F.;
Steiner, A.; Xiao, J. Org. Lett. 2006, 8, 215-218 and references therein.
(3) (a) Atkinson, R. C. J.; Gibson, V. C.; Long, N. J. Chem. Soc. ReV.
2004, 33, 313-328. (b) Colacot, T. J. Chem. ReV. (Washington, DC, U.S.)
2003, 3101-3118. (c) Richards, C. J.; Locke, A. J. Tetrahedron: Asymmetry
1998, 9, 2377-2407.
10.1021/jo061360t CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/23/2006
9572
J. Org. Chem. 2006, 71, 9572-9579

Enantiopure Lithium tert-Butylsulfinylferrocene
SCHEME 1. Diastereoselective Ortho-Lithiation
SCHEME 3. Preparation of Enantiopure Sulfoxide 4
TABLE 1. Synthesis of 6b by Metalation of Sulfoxide 4 and
Addition of Isopropyl-N-tosylimine 11b
alkyllithium
(equiv)
conversiona
(%)
entry
temp, time
drb
1
2
3
4
5
6
t-BuLi (1.5)
n-BuLi (1.1)
n-BuLi (1.1)
n-BuLi (1.1)
n-BuLi (1.1)
n-BuLi (1.1)
+ TMEDA (1)
-78 °C, 1.5 h
-78 °C, 1.5 h
-78 °C, 10 min
-40 °C, 1.5 h
rt, 1.5 h
43
56
56
51
55
52
85:15
89:11
90:10
80:20
70:30
88:12
SCHEME 2. Diastereoselective Ortho-Lithiation Followed
by Aldimine Addition
-78 °C, 1.5 h
a Measured by 1H NMR on δ of t-Bu of sulfinyl groups. b Measured by
1H NMR on δ of CHMe2 groups.
then employed: N-phosphinoyl14 (13; R2 ) POPh2) and
N-carbamoyl (12; R2 ) Boc).
N-Tosyl imines 11 were prepared from corresponding com-
mercial aldehydes in two steps according to Chemla’s proce-
dure15 (for 11a-c,e) or in one step (for 11d) according to
Proctor’s protocol (BF3‚Et2O, MS, reflux).16 A similar method
was used for the synthesis of aromatic N-Boc imines 12 (Scheme
4).17 The alkyl N-Boc imines could not be prepared using this
methodology (formation of enamine18 instead of imine during
the deprotonation step). They were generated in situ from
sulfone 10.19 Two N-phosphinoyl imines 13 have been synthe-
sized according to Jennings’s protocol (NEt3, TiCl4, 0 °C).20
Ferrocenyl sulfoxide (4) was first lithiated with t-BuLi (THF,
-78 °C, 1.5 h; entry 1), as indicated in a earlier paper21 and
reacted at -78 °C with N-tosyl imine 11b (R1 ) i-Pr) as a model
(Table 1). Conversion and dr were easily determined on the
crude product by 1H NMR, from the respective chemical shifts
of sulfinyl t-Bu and i-Pr methyl groups. Pleasingly, the
anticipated tosylamino-sulfoxides 6b were obtained but with
moderate conversion. These two diastereoisomers (6b) can be
easily separated by chromatography on silica gel. The yield was
improved using n-BuLi (THF, 0 °C then rt, 2 h; Table 1 entries
2-6). The reaction time can be reduced to 10 min (entry 3)
instead of 1.5 h. Surprisingly, the reactions seem to stall at
≈50% conversion, with the remainder of the material being
unreacted sulfinyl ferrocene. It might be the result of the
formation of an 1:1 organo-lithium heteroaggregate of the
desired lithiated product 5 with the starting material 4 (in the
presence of THF).22 However, the addition of TMEDA did not
induction was obtained with unsubstituted benzaldehyde. Sur-
prisingly, imines were not previously used as prochiral elec-
trophiles.
Our very recent observation of a diastereocontrolled addition
of benzenesulfinyl carbanions and analogues with imines10
prompted us to investigate ferrocenesulfinyl carbanions, with
respect to the attractive synthesis of new ligands for asymmetric
catalysis.
Here, we wish to report the reaction of alkyl- and aryl-
aldimines bearing various electron-withdrawing groups on the
nitrogen atom with the lithium derivative of (S)-tert-butylsulfi-
nylferrocene (Scheme 2).
Results and Discussion
The tert-butylsulfinyl ferrocene (4) is readily available in
enantiopure form from ferrocene and Ellman’s (S)-tert-butyl tert-
butanethiosulfinate11 (9) in one step as shown by Carretero and
his group.12 Using the procedure of Mueller-Wersterhoff13 (to
obtain monolithiated ferrocene), we prepared sulfoxide (S)-4
on a multigram scale in 66% yield (Scheme 3).
We chose imines bearing electron-withdrawing groups,
incorporating an oxygen atom susceptible to coordination with
the lithium atom, leading to potentially ordered transition states.
The reaction was first tested and optimized with N-tosyl imines
11. Other electron-withdrawing groups, easier to cleave, were
(7) For recent examples of 1,2-disubstituted sulfinylferrocenes: Kloet-
zing, R. J.; Knochel, P. Tetrahedron: Asymmetry 2006, 17, 116-123.
Seitzberg Jimmi, G.; Dissing, C.; Sotofte, I.; Norrby, P.-O.; Johannsen, M.
J. Org. Chem. 2005, 70, 8332-8337. Raghunath, M.; Gao, W.; Zhang, X.
Tetrahedron: Asymmetry 2005, 16, 3676-3681.
(8) See ref 6c.
(14) For a recent review: Weinreb, S. M.; Orr, R. K. Synthesis 2005,
1205-1227.
(15) Chemla, F.; Hebbe, V.; Normant, J.-F. Synthesis 2000, 75-77.
(16) McKay, W. R.; Proctor, G. R. J. Chem. Soc., Perkin Trans. 1 1981,
2435-2442.
(9) See ref 5a.
(17) (a) Kanazawa, A. M.; Denis, J.-N.; Greene, A. E. J. Org. Chem.
1994, 59, 1238-1240. (b) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem.
Soc. 2002, 124, 12964-12965.
(18) Mecozzi, T.; Petrini, M. Synlett 2000, 73-74.
(19) Petrini, M. Chem. ReV. 2005, 105, 3949-3977.
(20) Jennings, W. B.; Lovely, C. J. Tetrahedron 1991, 47, 5561-5568.
(21) Minie`re, S.; Reboul, V.; Metzner, P. ARKIVOC (GainesVille, FL,
U.S.) 2005, (xi), 161-177.
(10) Le Fur, N.; Mojovic, L.; Ple´, N.; Turck, A.; Reboul, V.; Metzner
P. J. Org. Chem. 2006, 71, 2609-2616.
(11) Weix, D. J.; Ellman, J. A. Org. Lett. 2003, 5, 1317-1320.
(12) Priego, J.; Manchen˜o, O. G.; Cabrera, S.; Carretero, J. C. J. Org.
Chem. 2002, 67, 1346-1353.
(13) Sanders, R.; Mueller-Westerhoff, U. T. J. Organomet. Chem. 1996,
512, 219-224.
J. Org. Chem, Vol. 71, No. 26, 2006 9573

Grach et al.
SCHEME 4. Preparation of Imines and Sulfones
a : R1 ) Me; b: R1 ) i-Pr; c: R1 ) Cy; d: R1 ) t-Bu; e: R1 ) Ph; f: R1 ) m-BrC6H4; g: R1 ) 3-Pyr; h: R1 ) p-NO2C6H4.
TABLE 2. Diastereoselective Addition of Aldimines on Lithiated (S)-4
a Measured by 1H NMR on δ of t-Bu of sulfoxide groups. b Determined by 1H NMR on crude product. c Calculated from the mass of each diastereoisomer.
1
d The reaction was carried out with 2 equiv of sulfinylferrocene, 2.2 equiv of n-butyllithium, and 1 equiv of sulfone. e Measured by H NMR on δ of t-Bu
of sulfoxide groups and based on sulfone. f Isolated yield based on sulfone.
have any beneficial effect on conversion (entry 6) or dr. The
best asymmetric induction (90:10 ratio; Table 1, entry 3) was
obtained when the addition was performed at -78 °C. These
optimized conditions were used for the following reactions.
Using the optimized conditions, we were able to prepare a
variety of amino sulfoxide derivatives 6 using other aliphatic
N-tosylimines (Table 2; entries 1-4). The reaction yields were
all around 55%.23
(R1 ) Me; 11a) led to only one diastereoisomer (Table 2, entry
1). In the aromatic series (Table 2, entry 5), a slightly better
conversion and yield were obtained, but a modest dr was
observed and we could not separate the two diastereoisomers
on silica gel. Two N-phosphinoylimines 13d-e were also tested
(Table 2, entries 6 and 7). They led to a single diastereoisomer,
1
according to the H NMR spectrum, with lower conversions
and yields. Compound 7d was especially unstable and could
not be fully characterized. Such phosphorylated imines are
very sensitive to hydrolysis;24 consequently, other aromatic or
alkyl groups were not tested and we decided to use another
oxygenated group on the nitrogen atom: the carbamoyl moiety
(Boc).
Surprisingly, the more hindered imine (R1 ) t-Bu; 11d) led
to the lowest dr (Table 2, entry 4) and the less hindered imine
(22) Gossage, R. A.; Jastrzebski, J. T. B. H.; van Koten, G. Angew.
Chem., Int. Ed. 2005, 44, 1448-1454.
(23) Amino sulfoxides have been surmised to be good ligands for any
metals present in the silica gel, leading to low yields: Pedersen, B.; Rein,
T.; Sotofte, I.; Norrby, P.-O.; Tanner, D. Collect. Czech. Chem. Commun.
2003, 68, 885-898.
(24) Arini, L. G.; Sinclair, A.; Szeto, P.; Stockman, R. A. Tetrahedron
Lett. 2004, 45, 1589-1591.
9574 J. Org. Chem., Vol. 71, No. 26, 2006

Enantiopure Lithium tert-Butylsulfinylferrocene
FIGURE 1. X-ray crystal structure for 6d, 6a, 6c, and 8e (50% thermal ellipsoids). For clarity hydrogen atoms are omitted except in the cases of
C*H and NH.
We explored the scope of the reaction first with alkyl groups
for R1 (entries 8-10). These alkyl N-Boc-imines were prepared
in situ from sulfones 10a-c by the action of an extra amount
of base (e.g., LiHMDS,25 NaH26) or by an excess of carbon
nucleophile.27 We first tried the following conditions: 2 equiv
of n-BuLi in the presence of 4 and subsequent addition of
sulfone 10b. Unfortunately, only the addition of n-BuLi to the
imine, formed in situ, was obtained. The same reaction was
observed with LDA as a base leading to the amidation adduct.28
Consequently, we chose to use only 1 equiv of n-BuLi with
compound 4 and then to use 2 equiv of the lithio derivative 5
with 1 equiv of sulfone 10a-c (Table 2, entries 8-10). The
corresponding aliphatic adducts 8a-c were obtained in good
yields (based on the sulfone) as single diastereoisomer. It is
important to note that the unreacted (SS)-tert-butylsulfinylfer-
rocene (4) can be recovered after chromatography on silica gel
(50-62% yield) and reused (er > 98/2). Various aromatic (Table
2, entries 11, 12, and 14) and heteroaromatic (entry 13) imines
12e-h were then used with success. As previously noted, only
one diastereoisomer was isolated in each case. The highest yield
was obtained with imine 12e (78%; Table 2, entry 11).
crystal29 of the major isomer (Figure 1).30 We observed that
the more hindered group, the tert-butyl on the asymmetric
carbon center, is positioned above the Cp ring, and it is
interesting to note that the sulfinyl tert-butyl group is thus
directed toward the iron atom. Consequently, a high tilting of
the sulfoxide substituent relative to the Cp plane (CpCentroid
-
C-S ) 18.68° or 0.565 Å out of the plane of Cp ring31) was
observed and can be associated with this 1,2-substitution. To
our knowledge, it constitutes the largest angle observed in the
sulfurated ferrocene derivative series so far.32 For the same
reasons, the two Cp rings are not parallel and an unusual tilt
angle of 10.4° was observed.31
We assume that the same configuration (SS,SFc,S) was
obtained for the other aliphatic derivatives 6. In order to see if
this congested conformation for 6 was similar in solution, we
decided to compare, for each diastereoisomer, the chemical shifts
of two protons: NH and C*H. They are in proximity to the
(29) Single crystals suitable for X-ray crystal analysis were obtained from
a concentrated solution of ethanol and by the slow diffusion of pentane.
(30) Crystal structure data for C26H35FeNO3S2: crystal size 0.6 × 0.1
× 0.1 mm3, orthorhombic, space group P212121, a ) 16.2321(3) Å, b )
17.8126(4) Å, c ) 18.5205(4) Å, V ) 5354.94(19) Å3, Z ) 8, µ ) 0.746
mm-1. 63 931 reflections collected. Refinement for 14 170 reflections and
655 parameters gave GOF ) 1.139, R1 ) 0.0349, and wR2 ) 0.1121.
Absolute structure parameter ) -0.011(10). Selected bond lengths (Å) and
angles (deg) on the first molecule of the asymmetric unit: C*-CCp, 1.510;
For compound 6d (R1 ) t-Bu, R2 ) Ts), we were able to
unambiguously establish the (SS,SFc,S) absolute configuration
of the stereocenters by X-ray diffraction analysis of a single
(25) Liao, W.-W.; Deng, X.-M.; Tang, Y. Chem. Commun. 2004, 1516-
1517.
S-O, 1.490; S-CCp, 1.779; C*-N, 1.477; N-C*-CCp, 110.8; O-S-CCp-
CCp, 125.5.
(26) Zawadzki, S.; Zwierzak, A. Tetrahedron Lett. 2004, 45, 8505-8506.
(27) Pesenti, C.; Bravo, P.; Corradi, E.; Frigerio, M.; Meille, S. V.;
Panzeri, W.; Viani, F.; Zanda, M. J. Org. Chem. 2001, 66, 5637-5640.
(28) For a recent example of an imine amidation reaction: Rowland, G.
B.; Zhang, H.; Rowland, E. B.; Chennamadhavuni, S.; Wang, Y.; Antilla,
J. C. J. Am. Chem. Soc. 2005, 127, 15696-15697.
(31) Measured on the first molecule of the asymmetric unit.
(32) 61 ferrocene derivatives with one adjacent sulfur atom were found
in the CSD (version 5.27; Nov, 2005) including 12 sulfinylferrocenes.
Among them, a similar case was observed with bis(sulfinyl)bisferrocene
(0.54 Å out of the plane of the Cp ring): Arraya´s, R. G.; Alonso, I.; Familiar,
O.; Carretero, J. C. Organometallics 2004, 23, 1991-1996.
J. Org. Chem, Vol. 71, No. 26, 2006 9575

Grach et al.
TABLE 3. Chemical Shift of Characteristic Protons of 6, 7, and 8 Derivatives
δ NH (ppm)
δ C*H (ppm)
entry
product (dr)
major
minor
∆δ
major
minor
∆δ
1
2
3
4
5
6
7
8
9
6a (>98/2)
6b (90/10)
6c (89/11)
6d (64/36)
7e (>98/2)
8a (>98/2)
8b (>98/2)
8c (>98/2)
8e (>98/2)
8f (>98/2)
8g (>98/2)
8h (>98/2)
8.28a
4.03a
5.54a
8.48a
8.38a
8.80a
2.94
3.02
3.73
4.77a
3.84a
0.93
0.89-0.93
0.01-0.03
5.36a
4.79-4.87a
4.44-4.48a
5.67-5.71b
4.85b
3.90-3.94a
4.47a
5.07a
5.80-5.83b
7.19b
6.22b
5.49b
6.14b
5.50b
6.98-7.00b
7.12-7.14b
7.13-7.16b
7.31-7.33b
6.48-6.50b
6.47b
10
11
12
6.48-6.57b
6.57b
a In CDCl3. b In acetone-d6
sulfinyl group, which is known to exert a strong anisotropic
effect.33 The values are summarized in Table 3.
In the aliphatic series of 6 (Table 3, entries 1-4), the chemical
shifts are consistent for each diastereoisomer (ΝΗ δ 5.07-5.54;
C*H δ 4.44-4.77) except for 6a (entry 1), whose NH appeared
significantly deshielded: 8.28 ppm as compared to ≈ 5.5 ppm.
Due to the low steric hindrance of the methyl group, we
suspected that this shielding was the consequence of a confor-
mation change. It was confirmed by X-ray diffraction analysis
of 6a (Figure 1).29,34 As expected, the (SS,SFc,S) absolute
configuration was observed. The tert-butyl group of the sul-
foxide is now located above the Cp ring. Surprisingly, the carbon
atom of the methyl group is almost in the plane of the Cp ring
(C-C*-CCp-CCp, 171.0°). This conformational preference can
be understood by two weak bondings: (i) a hydrogen one
between the NH and the sulfinyl oxygen (S(O)---NH, 2.053 Å;
N-H---O angle, 168.2°); (ii) and a CH-π stabilizing electrostatic
interaction35 between the phenyl ring of the tosyl group and
the C-H bond of the tert-butyl group (d ) 2.72 Å). On the
other hand, the NH group seems to be far away from the iron
atom (NH---Fe, 3.409 Å).36
FIGURE 2. Proposed conformation of the minor isomer of 6.
In the Boc series (compounds 8), the chemical shifts of NH
and C*H were also consistent and seemed to be in agreement
with chemical shifts for the major isomer of the tosyl series
(Table 3, entries 6-12). Consequently, we suppose that the same
asymmetric induction of the sulfinyl group took place leading
to the (SS,SFc,S) configuration. This was verified by chemical
correlation. The Boc group of compound 8b was easily39
deprotected by TFA.40 The reprotection by a tosyl group of the
resulting primary amine 14 can be readily accomplished in good
yield without compromising the integrity of the stereocenter
1
since the same H NMR spectrum of the major isomer of 6b
Unfortunately, we were not able to obtain the X-ray structure
of the minor isomer of 6. In all of the cases (6b-d), the two
isomers exhibited a spectacular difference of NH chemical shifts
(up to 3.73 ppm). To explain this, we propose the existence of
hydrogen bonding between the NH and the sulfinyl oxygen atom
(Figure 2) for the minor isomer.
was obtained (Scheme 5).41
Single crystals of compound 8e were obtained, and the
expected (SS,SFc,S) configuration was confirmed by X-ray
diffraction analysis (Figure 1).42 The phenyl group is on the
(37) Crystal structure data for C28H37FeNO3S2: crystal size 0.557 × 0.110
× 0.091 mm3, tetragonal, space group P4(1), a ) 11.8067(4) Å, b )
11.8067(4) Å, c ) 19.3721(7) Å, V ) 2700.43(16) Å3, Z ) 4, µ ) 0.743
mm-1. 11 5827 reflections collected. Refinement for 18 377 reflections and
464 parameters gave GOF ) 1.035, R1 ) 0.0271, and wR2 ) 0.0616.
Absolute structure parameter ) 0.001(4). Selected bond lengths (Å) and
angles (deg): C*-CCp, 1.5214(10); S-O, 1.5048(6); S-CCp, 1.7777(7);
C*-N, 1.4702(9); N-C*-CCp, 110.38(6); O-S-CCp-CCp, -1.3.
(38) Desiraju, G. R. Acc. Chem. Res. 1996, 29, 441-449.
The X-ray structure of 6c (major diastereoisomer) was also
obtained (Figure 1).37 With a more hindered alkyl group than
methyl, the cyclohexyl is now located on the same side of the
tert-butyl of the sulfinyl group. Unusually weak hydrogen
bonding between the C*H and the sulfinyl oxygen (S(O)---C*H,
2.529 Å; CsH---O angle, 124.8°) could be responsible for this
conformational preference.38
(39) No reaction occurred with H2SO4, and the starting material was
recovered: Strazzolini, P.; Misuri, N.; Polese, P. Tetrahedron Lett. 2005,
46, 2075-2078.
(33) Green, C. H.; Helleir, D. G. J. Chem. Soc., Perkin Trans. 2 1972,
458-463.
(40) Shendage, D. M.; Froehlich, R.; Haufe, G. Org. Lett. 2004, 6, 3675-
3678.
(41) Pallavicini, M.; Valoti, E.; Villa, L.; Piccolo, O. Tetrahedron:
Asymmetry 2001, 12, 1071-1075.
(34) Crystal structure data for C23H29FeNO3S2: crystal size 0.603 × 0.424
× 0.337 mm3, monoclinic, space group P21, a ) 9.7869(4) Å, b ) 11.2474-
(4) Å, c ) 10.5714(4) Å, V ) 1135.78(8) Å3, Z ) 2, µ ) 0.872 mm-1
.
37 257 reflections collected. Refinement for 15 183 reflections and 300
parameters gave GOF ) 1.081, R1 ) 0.0351, and wR2 ) 0.1029. Absolute
structure parameter ) 0.000(7). Selected bond lengths (Å) and angles
(deg): C*-CCp, 1.5152(18); S-O, 1.5123(12); S-CCp, 1.7600(13); C*-
N, 1.483(2); N-C*-CCp, 109.59(10); O-S-CCp-CCp, -1.3.
(42) Crystal structure data for C26H33FeNO3S: crystal size 0.521 × 0.199
× 0.142 mm3, orthorhombic, space group P212121, a ) 17.7483(14) Å, b
) 19.5715(16) Å, c ) 22.6086(18) Å, V ) 7853.3(11) Å3, Z ) 12, µ )
0.681 mm-1. 247 864 reflections collected. Refinement for 27 904 reflections
and 884 parameters gave GOF ) 1.080, R1 ) 0.0320, and wR2 ) 0.0855.
Absolute structure parameter ) -0.021(5). Selected bond lengths (Å) and
angles (deg) on the first molecule of the asymmetric unit: C*-CCp, 1.519;
(35) Nishio, M. Tetrahedron 2005, 61, 6923-6950.
(36) According to DFT-based conformational analyses of a number of
ferrocene containing alcohols, the FesH distance was between 2.61 and
2.95 Å: Vrcek, V.; Bu¨hl, M. Organometallics 2006, 25, 358-367.
S-O, 1.502; S-CCp, 1.766; C*-N, 1.465; N-C*-CCp, 111.1; O-S-CCp
-
CCp, -6.82.
9576 J. Org. Chem., Vol. 71, No. 26, 2006

Enantiopure Lithium tert-Butylsulfinylferrocene
SCHEME 5. Chemical Correlation
SCHEME 6. Synthesis of r-Ferrocenylalkylamine
SCHEME 7. Four-Membered (A), Pseudocyclic Chairlike (B), and Pseudocyclic Boatlike (C) Transition States in Tosyl Series
exo side of the ferrocene, but comparable to structure 6d, the
tert-butyl sulfinyl function is also located on the exo side of
the ferrocene. As in the 6c structure, this X-ray analysis showed
weak hydrogen bonding between the C*H and the sulfinyl
oxygen (S(O)---C*H, 2.288 Å; S-O---H angle, 135.85°).35
Other transformations have been performed in order to
synthesize an enantiopure R-ferrocenylalkylamine. An example
was given with the synthesis of amine (S)-16 in two steps
(Scheme 6): reductive cleavage of the stereogenic sulfur moiety
with Raney nickel43 and then deprotection of the tosyl group
by SmI2.44 The enantiopurity of 15 and 16,45 er 99:1 (chiral
HPLC), confirmed that no epimerization occurred during this
process.46
the following: (i) The sulfoxide and the lithium atom form a
flat five-membered ring, coplanar with the Cp ring. (ii) One of
the ring faces is clearly hindered by the iron atom, which is
linked to the second Cp ring. Consequently, the approach of
the imine from the exo side of the ferrocene will be preferred.
(iii) The imine has an (E)-configuration in which the tolyl group
is anti to the NdC bond (along the NsS bond).47
Examination of possible approaches of the sulfinyl carbanion
and the imine led us to consider a concerted four-membered
transition state A, as first proposed by Garcia Ruano’s group48
and then by us (Scheme 7).10 It cannot be applied in the
ferrocene series. Indeed, when a coordination of the lithium atom
with both the tert-butylsulfinyl oxygen atom and one of the two
sulfonylimine oxygen (or Boc oxygen) atoms takes place, the
To explain the homogeneous stereochemical sense (all SS,SFc,S
configurations), we tried to build transition states. We supposed
(46) (a) Herrmann, R.; Huebener, G.; Siglmueller, F.; Ugi, I. Liebigs
Ann. Chem. 1986, 251-268. (b) Cushman, M.; Chen, J. K. J. Org. Chem.
1987, 52, 1517-1521.
(43) D’Antona, N.; Lambusta, D.; Morrone, R.; Nicolosi, G.; Secundo,
F. Tetrahedron: Asymmetry, 2004, 3835-3840.
(44) Kuriyama, M.; Soeta, T.; Hao, X.; Chen, Q.; Tomioka, K. J. Am.
Chem. Soc. 2004, 126, 8128-8129.
(47) Charette, A. B.; Giroux, A. Tetrahedron Lett. 1996, 37, 6669-
6672.
(45) Racemic 16 was prepared in four steps according to an adapted
procedure from: Woltersdorf, M.; Kranich, R.; Schmalz, H.-G. Tetrahedron
1997, 53, 7219-7230.
(48) (a) Garcia, Ruano, J. L.; Alema´n, J.; Soriano, J. F. Org. Lett. 2003,
5, 677-680. (b) Garcia Ruano, J. L.; Alema´n J. Org. Lett. 2003, 5, 4513-
4516.
J. Org. Chem, Vol. 71, No. 26, 2006 9577

Grach et al.
SCHEME 8. Pseudocyclic Boatlike Transition States in the Boc Series
model does not lead to the observed configuration. It appears
that this approach is disfavored by a strong steric interaction
between the R1 and t-Bu groups.
cenylaryl-amines are not easy to prepare.51 These derivatives
were used as ligands in asymmetric synthesis52 and were
demonstrated to be better enantioselective ligands for some
reactions.53 Also, this opens the way to a growing class of
bidentate ligands with both nitrogen and sulfur coordination sites
for asymmetric catalysis.54
Further application can also be undertaken. In particular, the
synthesis of 1,1′,2-trisubstituted ferrocene derivatives via a
second metalation-alkylation sequence with compounds 8
bearing a Boc group.55
We excluded a pseudocyclic chairlike transition state B
(Scheme 7) due to severe electrostatic and steric interactions
between the tert-butylsulfinyl and the sulfonyl groups.
Another model allowed us to remove all of the preceding
interactions by placing the tolylsulfonyl group and sulfinyl
groups far apart. Coordination of the lithium atom to the oxygen
atoms of both the sulfinyl and sulfonyl groups may force the
transition state to adopt a pseudocyclic boatlike transition state
C. It leads to the (SS,SFc,S) diastereoisomer, in agreement with
the experiment (Scheme 7). When the R1 group was hindered
(R1 ) Cy, i-Pr, t-Bu), a possible steric interaction with the Cp
ring could have counterbalanced the previous effect and
explained the lower selectivity.
In the Boc series, the same type of model D can be proposed,
involving a coordination between the carbonyl of the Boc group
and the lithium atom (Scheme 8). According to the sp2
hybridization of the carbonyl group, instead of the sp3 arrange-
ment of the sulfonyl function, the steric interaction between the
Cp ring and the R1 group should be lower and explain the better
asymmetric induction.
Experimental Section
General Procedure for Addition of Imines on (SS)-tert-
Butylsulfinylferrocene (4). To a cold solution (0 °C) of (SS)-tert-
butylsulfinylferrocene (4) (1 equiv) in dry THF (2 mL for 50 mg
of 4) was added n-BuLi (in hexanes; 1.1 equiv). The mixture was
stirred for 2 h at room temperature, and the solution was cooled at
-78 °C. The imine (1 equiv) in dry THF (1.5 mL for 50 mg of
imine) was added slowly. The reaction mixture was stirred at -78
°C. After completion, a 10% water solution in THF (2 mL for 50
mg of 4) was added at -78 °C. The reaction mixture was warmed
at room temperature, then water (2 mL for 50 mg of 4) was added.
The aqueous layer was extracted with Et2O (2 mL for 50 mg of 4).
The combined organic layers were dried over MgSO4 and then
evaporated to dryness.
(SFc,SS)-2-(N-Tosyl-1-amino-2-methylpropyl)-1-tert-butylsulfi-
nylferrocene (6b). The reaction was performed on 250 mg (0.86
mmol) of (SS)-t-butylsulfinylferrocene (4) and 194 mg (0.86 mmol)
Conclusion
The results reported here provide a nice entry to new
2-aminoalkyl or aminoaryl ferrocenyl tert-butylsulfoxides (6-
8). The sequence is rather straightforward, only two steps from
ferrocene, and it is very practical. Though the yields were
moderate, the unreacted (SS)-tert-butylsulfinylferrocene (4) was
recovered after purification.
The closest precedent for structures 6-8 in literature was
from the Bonini group49 who investigated the asymmetric
synthesis of aminoalkyl-ferrocenyl sulfides by the reaction of
enantiomerically pure (S)-2-iminoalkyl-ferrocenyl p-tolylsulfide
with organometallic reagents in the presence of a Lewis acid.
A very nice asymmetric induction was observed (in favor of
S,SFc). However, this method required the synthesis of the
starting material in three steps and, moreover, partial reduction
of the imine was observed.
Compared to the Ugi’s methodology leading to (SS,RFc,S)
configurations,50 our method allowed the synthesis of the other
diastereoisomer.
Compounds 6-8 are potential precursors of a range of new
ferrocene derivatives. Enantiopure 1-ferrocenylalkyl- (in par-
ticular with an alkyl group different from methyl) and 1-ferro-
(51) (a) Yasuike, S.; Kofink, C. C.; Kloetzing, R. J.; Gommermann, N.;
Tappe, K.; Gavryushin, A.; Knochel, P. Tetrahedron: Asymmetry 2005,
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Tetrahedron: Asymmetry 2000, 11, 4083-4091.
(52) (a) Dai, H.; Hu, X.; Chen, H.; Bai, C.; Zheng, Z. J. Mol. Catal. A:
Chem. 2004, 211, 17-21. (b) Hu, X.; Dai, H.; Bai, C.; Chen, H.; Zheng,
Z. Tetrahedron: Asymmetry 2004, 15, 1065-1068. (c) Tappe, K.; Knochel,
P. Tetrahedron: Asymmetry 2004, 15, 91-102.
(53) (a) Hu, X.; Chen, H.; Dai, H.; Hu, X.; Zheng, Z. Tetrahedron:
Asymmetry 2003, 14, 2073-2080. (b) Hu, X.; Chen, H.; Dai, H.; Zheng,
Z. Tetrahedron: Asymmetry 2003, 14, 3415-3421. (c) Hu, X.; Dai, H.;
Hu, X.; Chen, H.; Wang, J.; Bai, C.; Zheng, Z. Tetrahedron: Asymmetry
2002, 13, 1687-1693. (d) Hu, X.; Chen, H.; Hu, X.; Dai, H.; Bai, C.; Wang,
J.; Zheng, Z. Tetrahedron Lett. 2002, 43, 9179-9182. (e) Fukuda, T.;
Takehara, A.; Iwao, M. Tetrahedron: Asymmetry 2001, 12, 2793-2799.
(f) Dubner, F.; Knochel, P. Tetrahedron Lett. 2000, 41, 9233-9237. (g)
Schwink, L.; Knochel, P. Chem.sEur. J. 1998, 4, 950-968. (h) Schwink,
L.; Ireland, T.; Puntener, K.; Knochel, P. Tetrahedron: Asymmetry 1998,
9, 1143-1163. (i) Ohno, A.; Yamane, M.; Hayashi, T.; Oguni, N.; Hayashi,
M. Tetrahedron: Asymmetry 1995, 6, 2495-2502.
(54) (a) Gerard, S.; Pressel, Y.; Riant, O. Tetrahedron: Asymmetry 2005,
16, 1889-1891. (b) Anderson, J. C.; Osborne, J. Tetrahedron: Asymmetry
2005, 16, 931-934. (c) Cabrera, S.; Gomez, Arrayas, R.; Alonso, I.;
Carretero, J. C. J. Am. Chem. Soc. 2005, 127, 17938-17947. (d) Mancheno,
O. G.; Arrayas, R. G.; Carretero, J. C. Organometallics 2005, 24, 557-
561. (e) Hu, X.; Bai, C.; Dai, H.; Chen, H.; Zheng, Z. J. Mol. Catal. A:
Chem.2004, 218, 107-112. (f) Tu, T.; Zhou, Y.-G.; Hou, X.-L.; Dai, L.-
X.; Dong, X.-C.; Yu, Y.-H.; Sun, J. Organometallics 2003, 22, 1255-
1265. (g) Dai, L.-X.; Tu, T.; You, S.-L.; Deng, W.-P.; Hou, X.-L. Acc.
Chem. Res. 2003, 36, 659-667. (h) Karlstro¨m, A. S. E.; Huerta, F. F.;
Meuzelaar, G. J.; Ba¨ckvall, J.-E. Synlett 2001, 923-926. (i) You, S.-L.;
Zhou, Y.-G.; Hou, X.-L.; Dai, L. X. Chem. Commun. 1998, 2765-2766.
(55) Chong, J. M.; Hegedus, L. S. Organometallics 2004, 23, 1010-
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(49) Bernardi, L.; Bonini, B. F.; Capito`, E.; Dessole, G.; Femoni, C.;
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(50) (a) Wang, C.-H.; Brubaker, C. H. J. J. Mol. Catal. A: Chem. 1992,
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9578 J. Org. Chem., Vol. 71, No. 26, 2006

Enantiopure Lithium tert-Butylsulfinylferrocene
of imine 11b. The mixture was stirred 15 min at -78 °C. The crude
product was purified by column chromatography, using dichlo-
romethane/ethyl acetate (9/1) as eluent, to afford two diastereo-
isomers (56%, dr ) 90:10). The major diastereoisomer (SFc,SS,S)-
6b was isolated as a yellow solid (226 mg, Rf ) 0.50 with
dichloromethane/ethyl acetate 9:1): [R]D20 ) -6,4 (c ) 1, CHCl3);
mp 124 °C; IR (KBr) ν 1462, 1325, 1157 cm-1; 1H NMR (CDCl3,
400 MHz) δ 7.86 (d, 2H, J ) 8.3 Hz, Ar), 7.29 (d, 2H, J ) 8.3
Hz, Ar), 5.54 (d, 1H, J ) 6.8 Hz, NH), 4.77 (dd, 1H, J ) 6.8, J )
3.1 Hz, CH-N), 4.44 (s, 5H, Cp), 4.31-4.40 (m, 3H, Cp), 2.41 (s,
3H, Me), 2.19-2.25 (m, 1H, CH of i-Pr), 1.16 (s, 9H, t-Bu), 0.73
(d, 3H, J ) 7.0 Hz, Me of i-Pr), 0.68 (d, 3H, J ) 7.0 Hz, Me of
i-Pr); 13C NMR (CDCl3, 100.6 MHz) δ 143.2 (Ar), 139.2 (Ar),
129.8 (2C, Ar), 127.8 (2C, Ar), 93.2 (Cp), 82.0 (Cp), 72.0 (5C,
Cp), 69.4 (Cp), 69.0 (Cp), 68.6 (Cp), 57.4 (Cquat t-Bu), 56.7 (CH-
N), 34.0 (CH of i-Pr), 24.1 (3C, C t-Bu), 21.9 (Me of Ts), 20.0
(Me of i-Pr), 16.7 (Me of i-Pr); HRMS (ESI) Calcd for C25H34-
FeNO3S2 (MH+): 516.1330. Found: 516.1317. Anal. Calcd for
C25H33FeNO3S2: C, 58.25; H, 6.45; N, 2.72. Found: C, 58.49; H,
6,84; N, 3.10. The minor diastereoisomer (SFc,SS,R)-6b was isolated
as a yellow oil (27 mg, Rf ) 0.85 with dichloromethane/ethyl acetate
by column chromatography with n-heptane/ethylacetate (8/2) gave
(S)-15 as a yellow oil (75 mg, 65%): [R]D ) +32.0 (c ) 1,
20
CHCl3); er >99:1 by HPLC (Daicel AD-H column 250 × 4.6
(length × inside diameter)) 5 µm, 95:5 n-heptane/propan-2-ol at 1
mL min-1, 203 nm, 20 °C; tR ) 19.97 min (R), tR ) 38.37 min
1
(S); H NMR (CDCl3, 400 MHz) δ 7.83 (d, 2H, J ) 8.4 Hz, Ar),
7.34 (d, 2H, J ) 8.4 Hz, Ar), 4.95 (d, 1H, J ) 4.8 Hz, NH), 4.00-
4.13 (m, 10H, CH-N and Cp), 2.45 (s, 3H, Me), 2.01-2.09 (m,
1H, CH of i-Pr), 0.69 (d, 3H, J ) 6.8 Hz, Me of i-Pr), 0.63 (d, 3H,
J ) 7.2 Hz, Me of i-Pr); 13C NMR (CDCl3, 100.6 MHz) δ 143.8
(Ar), 138.7 (Ar), 130.1 (2C, Ar), 127.5 (2C, Ar), 88.1 (Cp), 69.3
(5C, Cp), 69.2 (Cp), 68.2 (Cp), 67.9 (Cp), 66.7 (Cp), 59.2 (CH-
N), 31.9 (CH of i-Pr), 22.0 (Me of Ts), 19.1 (Me of i-Pr), 17.3
(Me of i-Pr); HRMS (ESI) Calcd for C21H26FeNO2S (MH+):
412.1034. Found: 412.1029.
(S)-1-Ferrocenyl-2-methyl-propylamine (16). To a 0.1 M THF
solution of SmI2 (8.76 mL, 0.876 mmol) and HMPA (0.58 mL)
was added a solution of (S)-15 (30 mg, 0.073 mmol) in THF (0.35
mL) at room temperature. The whole mixture was stirred under
reflux for 12 h (the purple color of the solution disappeared). The
mixture was quenched with saturated NaCl (10 mL). The aqueous
layer was extracted with ether (2 × 10 mL). The combined organic
layers were washed with sat. NaHCO3 (10 mL) and sat. NaCl (10
mL) and then dried over MgSO4. Evaporation of the solvent and
purification by column chromatography with ethylacetate gave (S)-
1
9:1): IR (KBr) ν 1458, 1318, 1151 cm-1; H NMR (CDCl3, 400
MHz) δ 8.48 (d, 1H, J ) 8.6 Hz, NH), 7.77 (d, 2H, J ) 8.3 Hz,
Ar), 7.21 (d, 2H, J ) 8.3 Hz, Ar), 4.50 (s, 5H, Cp), 4.26-4.32 (m,
3H, Cp), 3.84 (dd, 1H, J ) 10.2, J ) 8.6 Hz, CH), 2.32 (s, 3H,
Me), 1.59-1.66 (m, 1H, CH of i-Pr), 1.12 (s, 9H, t-Bu), 0.47 (d,
3H, J ) 7.0 Hz, Me of i-Pr), 0.43 (d, 3H, J ) 7.0 Hz, Me of i-Pr);
13C NMR (CDCl3, 100.6 MHz) δ 141.8 (Ar), 141.4 (Ar), 129.1
(2C, Ar), 126.5 (2C, Ar), 94.1 (Cp), 79.9 (Cp), 73.3 (Cp), 71.8
(5C, Cp), 68.8 (Cp), 68.2 (Cp), 61.3 (CH-N), 57.4 (Cquat t-Bu),
36.5 (CH of i-Pr), 23.7 (3C, C t-Bu), 21.7 (Me of Ts), 21.4 (Me of
i-Pr), 21.0 (Me of i-Pr).
General Procedure for Addition of Sulfones (10) on (SS)-t-
Butylsulfinylferrocene (4). To a cold solution (0 °C) of (SS)-tert-
butylsulfinylferrocene (4) (2 equiv) in dry THF (2 mL for 50 mg
of 4) was added n-BuLi (in hexanes; 2.2 equiv). The mixture was
stirred for 2 h at room temperature, and the solution was cooled at
-78 °C. The appropriate sulfone 10 (1 equiv) in dry THF was added
dropwise. The reaction mixture was stirred at -78 °C. After
completion, a 10% water solution in THF (2 mL for 50 mg of 4)
was added at -78 °C. The reaction mixture was warmed at room
temperature, then water (2 mL for 50 mg of 4) was added. The
aqueous layer was extracted with Et2O (2 mL for 50 mg of 4). The
combined organic layers were dried over MgSO4 and then
evaporated to dryness.
20
16 as a yellow oil (13 mg, 70%): [R]D ) +89.2 (c ) 0.325,
C6H6); lit. [R]D20 ) -89.7 (c ) 1.0, C6H6) for (R)-16;42 er 99:1 by
HPLC (Daicel AD column 250 × 4.6 (length × inside diameter))
10 µm, 100% CH3CN at 1 mL min-1, 201 nm, 20 °C; tR ) 13.3
min (R), tR ) 37.6 min (S); 1H NMR (CDCl3, 400 MHz) δ 4.19-
4.21 (m, 1H, Cp), 4.16 (s, 5H, Cp), 4.07-4.13 (m, 3H, Cp), 3.47
(d, J ) 5.0 Hz, CH-N), 1.74 (br, 2H, NH2), 1.57-1.69 (m, 1H,
CH of i-Pr), 0.85 (d, 3H, J ) 8.0 Hz, Me of i-Pr), 0.79 (d, 3H, J
) 8.0 Hz, Me of i-Pr); 13C NMR (CDCl3, 62.9 MHz) δ 93.8, 68.2,
67.0, 65.2, 56.5, 35.2, 18.9, 18.6.
Acknowledgment. We thank the “PunchOrga” Network
(Poˆle Universitaire Normand de Chimie Organique), the “Re´gion
Haute-Normandie”, the “Re´gion Basse-Normandie”, the “Min-
iste`re de la Recherche”, CNRS (Centre National de la Recherche
Scientifique), and the European Union (FEDER funding) for
financial support. We also thank Aure´lie Faliez and Virginie
Tronel (IUT-Rouen) for their contribution to this work.
Supporting Information Available: Experimental procedures
and characterization for all new compounds described in this work
and crystallographic data for the reported structures (CIF format).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(S)-1-Ferrocenyl-2-methyl-N-tosyl-propylamine (15). To a
solution of Raney nickel (1 g, previously rinsed with water, ethanol,
and then methanol) in methanol (10 mL) was added (SFc,SS,S)-6b
(150 mg, 0,29 mmol), and the whole mixture was stirred under
reflux for 2 h. The mixture was cooled, filtered off through celite,
and rinsed with ethanol. Evaporation of the solvent and purification
JO061360T
J. Org. Chem, Vol. 71, No. 26, 2006 9579