2-Amino-substituted 1-sulfinylferrocenes as chiral ligands in the addition of diethylzinc to aromatic aldehydes

Article abstract of DOI:10.1021/jo016271p

A simple and modulable access to a structural variety of enantiopure amino-substituted ferrocenyl sulfoxides and their use as chiral catalysts in the asymmetric addition of diethylzinc to aromatic aldehydes is described. Moderate to high enantioselectivit

Full text of DOI:10.1021/jo016271p

1
346
J . Org. Chem. 2002, 67, 1346-1353
2
-Am in o-Su bstitu ted 1-Su lfin ylfer r ocen es a s Ch ir a l Liga n d s in th e
Ad d ition of Dieth ylzin c to Ar om a tic Ald eh yd es
J uli a´ n Priego, Olga Garc ´ı a Manche n˜ o, Silvia Cabrera, and J uan Carlos Carretero*
Departamento de Qu ı´ mica Org a´ nica, Facultad de Ciencias, Universidad Aut o´ noma de Madrid,
2
8049, Madrid, Spain
juancarlos.carretero@uam.es
Received November 7, 2001
A simple and modulable access to a structural variety of enantiopure amino-substituted ferrocenyl
sulfoxides and their use as chiral catalysts in the asymmetric addition of diethylzinc to aromatic
aldehydes is described. Moderate to high enantioselectivities (up to 96% ee) were obtained in the
case of the arylsulfonamide ligands (RFc, R
S S
)-4h and (RFc, R )-4i. It has been demonstrated that
the planar chirality of the ferrocene unit is the decisive chiral element involved in the reaction.
In tr od u ction
Chiral nonracemic sulfoxides have long been employed
In this context, we describe herein the synthesis of
enantiopure 2-amino-substituted 1-sulfinylferrocenes as
a new family of sterically and electronically modulable
ligands, having central (sulfur atom) and planar chirality
ferrocene unit), as well as catalytic effectiveness in the
6
as efficient stereochemical controllers in many classical
1
keystone C-C bond-forming reactions, such as Diels-
(
Alder reactions, 1,3-dipolar cycloadditions, 1,2-additions
to carbonyls, and conjugate additions, and more recently
have also been applied in several transition metal-
asymmetric addition of diethylzinc to aromatic alde-
7
hydes. To the best of our knowledge, there are very few
precedents dealing with the use of sulfoxides as chiral
ligands in this kind of reaction, the enantioselectivity of
2
catalyzed reactions. However, despite the outstanding
chemical importance and industrial interest in developing
8
the process being very modest (ee in the range 2-55%).
3
catalytic enantioselective methods, compared to the
stoichiometric-based chiral auxiliary approach,1 very few
studies on the use of sulfoxides as chiral ligands for
asymmetric synthesis have been reported to date, most
of them dealing with asymmetric palladium-catalyzed
allylic substitutions.4 Among the plethora of chiral
,2
Resu lts a n d Discu ssion
Syn th esis of En a n tiop u r e ter t-Bu tylsu lfin ylfer -
r ocen es. Taking into account that the tert-butylsulfinyl
group proved to be an excellent chiral auxiliary in our
previous studies on asymmetric intramolecular Pauson-
3
structural motifs used in asymmetric catalysis, enan-
2
f
tiopure 1,2-disubstituted ferrocenes have received great
Khand reactions of 1-sulfinylenynes, we considered that
this type of sterically encumbered sulfoxide could be a
reasonable starting point for the design of chiral ligands
5
attention in recent years. It has been well demonstrated
that the planar chirality of this type of compounds can
provide an appropriate chiral environment for asym-
metric induction, especially when ferrocenes having P,P-,
P,N-, or N,O-bidentate metal-coordinating substituents
are employed.5
(4) (a) Hiroi, K.; Watanabe, K.; Abe, I.; Koseki, M. Tetrahedron Lett.
2
001, 42, 7617. (b) Hiroi, K.; Suzuki, Y., Abe, I.; Kawagishi, R.
Tetrahedron 2000, 56, 4701. (c) Petra, D. G. I.; Kamer, P. C. J .; Spek,
A. L.; Schoemaker, H. E.; van Leeuwen, P. W. N. M. J . Org. Chem.
2
000, 65, 3010. (d) Hiroi, K.; Suzuki, Y.; Kawagishi, R. Tetrahedron
Lett. 1999, 40, 715. (e) Hiroi, K.; Suzuki, Y.; Abe, I.; Hasegawa, Y.;
Suzuki, K. Tetrahedron: Asymmetry 1998, 9, 3797. (f) Hiroi, K.; Suzuki,
Y. Tetrahedron Lett. 1998, 39, 6499. (g) Hiroi, K.; Suzuki, Y. Hetero-
cycles 1997, 46, 77. (h) Tokunoh, R.; Sodeoka, M.; Aoe, K.-I.; Shibasaki,
M. Tetrahedron Lett. 1995, 36, 8035. (i) Hiroi, K.; Onuma, H.; Arinaga,
Y. Chem. Lett. 1995, 1099. (j) Allen, J . V.; Bower, J . F.; Williams, J .
M. J . Tetrahedron: Asymmetry 1994, 5, 1895. (k) Khiar, N.; Fern a´ ndez,
I.; Alcudia, F. Tetrahedron Lett. 1993, 34, 123. See also: (l) Owens, T.
D.; Hollander, F. J .; Oliver, A. G.; Ellman, J . A. J . Am. Chem. Soc.
2001, 123, 1539.
*
To whom correspondence should be addressed. Fax: 34 91
973966; tel: 34 91 3973925.
1) Recent reviews: (a) Garcia Ruano, J . L.; Cid de la Plata, B. Top.
3
(
Curr. Chem., 1999, 204, 1. (b) Baird, C. P.; Rayner, C. M. J . Chem.
Soc., Perkin Trans. 1 1998, 1973. (c) Aversa, M. C.; Barattucci, A.;
Bonaccorsi, P.; Gianneto, P. Tetrahedron: Asymmetry 1997, 8, 1339.
(
d) Carre n˜ o, C. Chem. Rev. 1995, 95, 1717.
(2) Recent references: (a) D ´ı az Buezo, N.; de la Rosa, J . C.; Priego,
J .; Alonso, I.; Carretero, J . C. Chem. Eur. J . 2001, 7, 3890. (b) Hiroi,
K.; Suzuki, Y.; Kato, F.; Kyo, Y. Tetrahedron: Asymmetry 2001, 12,
(5) For
a general account, see: (a) Ferrocenes: Homogeneous
3
2
1
7. (c) D ´ı az Buezo, N.; Garc ´ı a Manche n˜ o, O.; Carretero, J . C. Org. Lett.
000, 2, 1451. (d) Hiroi, K.; Yamada, A. Tetrahedron: Asymmetry 2000,
1, 1835. (e) Montenegro, E.; Moyano, A.; Peric a` s, M. A.; Riera, A.;
Catalysis. Organic Synthesis. Material Science; Hayashi, T.; Togni, A.
Eds.; VCH: Weinheim, Germany, 1995. For recent reviews, see: (b)
Richards, C. J .; Locke, A. J . Tetrahedron: Asymmetry 1998, 9, 2377.
(c) Kagan, H. B.; Riant, O. Advances in Asymmetric Synthesis; Hassner,
A., Ed.; J AI Press Inc: Greenwich, CT, 1997; Vol. 2., pp 189-235. (d)
Togni, A. Angew. Chem., Int. Ed. Engl. 1996, 35, 1475.
Alvarez-Larena, A.; Piniella, J .-F. Tetrahedron: Asymmetry 1999, 10,
57. (f) Adrio, J .; Carretero, J . C. J . Am. Chem. Soc. 1999, 121, 7411.
g) Priego, J .; Carretero, J . C. Synlett 1999, 1603. (h) Paley, R. S.; Rubio,
4
(
M. B.; Fern a´ ndez de la Pradilla, R.; Dorado, R.; Hundal, G.; Mart ´ı nez-
Ripoll, M. Organometallics 1996, 15, 4672. (i) Villar, J . M.; Delgado,
A.; Llebaria, A.; Moret o´ , J . M. Tetrahedron: Asymmetry 1995, 6, 665.
(6) Previous communication: Priego, J .; Garc ´ı a Manche n˜ o, O.;
Cabrera, S.; Carretero, J . C. Chem. Commun. 2001, 2026.
(7) For reviews, see: (a) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101,
757. (b) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley:
New York, 1994; Chapter 5. (c) Knochel, P.; Singer, R. D. Chem. Rev.
1993, 93, 2117. (d) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833.
(8) (a) Chelucci, G.; Berta, D.; Saba, A. Tetrahedron 1997, 53, 3843.
(b) Carre n˜ o, M. C.; Garc ´ı a Ruano, J . L.; Maestro, M. C.; Mart ´ı n
Cabrejas, L. M. Tetrahedron: Asymmetry 1993, 4, 727.
(
j) Hiroi, K.; Arinaga, Y. Tetrahedron Lett. 1994, 35, 153.
(3) General references: (a) Catalytic Asymmetric Synthesis, 2nd ed.;
I. Ojima, Ed.; VCH: New York, 2000. (b) Comprehensive Asymmetric
Catalysis; J acobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
Berlin, 1999. (c) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
J ohn Wiley & Sons: New York, 1994.
1
0.1021/jo016271p CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/24/2002

2
-Amino-Substituted 1-Sulfinylferrocenes
J . Org. Chem., Vol. 67, No. 4, 2002 1347
Sch em e 1
Sch em e 3
Sch em e 2
oxygen coordinates the lithium atom and the large tert-
butyl group is opposite to the iron atom.13 Although many
examples of trapping of this lithiated species with dif-
ferent electrophiles have been described (>96% de), as
far as we know the use of nitrogen electrophiles had
not been previously reported. We found that the depro-
tonation of (R)-1 with n-BuLi (THF, 0 °C) and further
addition of tosyl azide led to the intermediate ferro-
cenyl azide 3. This compound was not isolated and was
based on sulfinyl-substituted ferrocenes. Optically pure
tert-butysulfinylferrocene [(S)-1] was previously prepared
by Kagan et al. from the commercially available enan-
tiopure sulfite I by two consecutive nucleophilic configu-
1
4
9
rational inversions at the sulfur atom: treatment of I
with t-BuMgCl to give the tert-butylsulfinate II, followed
by further reaction with ferrocenyllithium (Scheme 1).
The same group has also reported that (R)-1 can be
obtained in high optical purity by asymmetric oxidation
in situ reduced with NaBH
4
under phase-transfer reac-
N I, H O-THF) to provide the
)-4a as the only isolated diaste-
tion conditions15 (Bu
aminoferrocene (RFc,R
+
4
2
S
reomer (64% overall yield after flash chromatography).
Starting from enantiopure (R)-1 (g99% ee), we confirmed
that the optical purity of the resulting aminoferrocene
of tert-butylsulfenylferrocene under appropriate reaction
i
conditions [cumene hydroperoxide, Ti(O Pr)
4
, (R,R)-DET,
1
0
H
2
O, CH
2 2
Cl ].
4
a was also very high (>98% ee, HPLC, Chiralpak AS
As an alternative method, we have developed a simple
column), proving that the overall procedure occurred
without any previous epimerization at the sulfur atom
one-step synthesis of (R)-1 based on the direct sulfiny-
lation of ferrocenyllithium (formed in situ by deprotona-
tion of ferrocene with t-BuLi in THF) with (R)-S-tert-butyl
(Scheme 3).
The ready access to different series of ligands with
1
1
1
,1-dimethylethanethiosulfinate 2 (Ellman’s reagent).
This procedure is experimentally quite simple (THF, 0
C) and occurs with inversion at the sulfur atom, provid-
modulable steric and electronic properties around the
metal-coordinating atom is of crucial importance in
enantioselective catalysis. Thus, having developed a
practical procedure for the preparation of enantiopure 4a
in gram quantities from ferrocene, the amino group was
transformed into a variety of nitrogen derivatives, such
as dialkyl-substituted amines (4b), alkyl- and aryl-
substituted amides (4c-f), and alkyl- and aryl-substi-
tuted sulfonamides (4g-l), following straighforward
reactions of amine derivatization (Scheme 4). From a
practical point of view, it is important to note that all
compounds 4 are very stable solids that are readily
purified by flash chromatography or recrystallization.
En a n tioselective Ad d ition s. With this sterically and
electronically varied set of enantiopure sulfinylferrocenes
in hand, we examined their efficiency as chiral catalysts
in the enantioselective addition of diethylzinc to alde-
hydes. Because of its experimental simplicity and the fact
that the reaction is effectively catalyzed by a wide variety
of Lewis bases, this type of C-C bond forming transfor-
mation is one of the most popular reactions in ligand
°
ing (R)-1 in 40% yield after flash chromatography (58%
of starting ferrocene is recovered, Scheme 2). Due to the
somewhat tedious preparation of (R)-2 in enantiopure
form,12 we have found that it is experimentally more
practical to use (R)-2 with an enantiopurity of about 80%,
followed by a single recrystallization (from 1:1 hexane:
2
Et O) of the resulting sulfinylferrocene (R)-1. By this way
gram quantities of almost enantiopure (R)-1 (g99% ee,
HPLC, Daicel Chiralcel OD column) have been routinely
obtained in a completely reproducible manner.
9
10a
It is well-known from the work of Kagan and Hua
that the ortho-lithiation of tert-butylsulfinylferrocene 1
occurs with complete diastereocontrol to generate the
ortho-lithiated intermediate III, in which the sulfinylic
(
9) Rebi e` re, F.; Riant, O.; Ricard, L.; Kagan, H. B. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 568.
10) (a) Lagneau, N. M.; Chen, Y.; Robben, P. M.; Sin, H.-S.; Takasu,
K.; Chen, J .-S.; Robinson, P. D.; Hua, D. H. Tetrahedron 1998, 54, 7301.
b) Diter, P.; Samuel, O.; Taudien, S.; Kagan, H. B. Tetrahedron:
Asymmetry 1994, 5, 549.
11) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J .; Ellman, J . A. J .
Am. Chem. Soc. 1998, 120, 8011.
12) Following the experimental procedure described in ref 11, in
(
(
(
(13) For diastereoselective ortho-deprotonation of ferrocenyl sulfox-
imines, see: Bolm, C.; Kesselgruber, M.; Mu n˜ iz, K.; Raabe, G.
Organometallics 2000, 19, 1648.
(
our hands, the preparation of (R)-2 with an enantiomeric excess higher
than 95% required four or more successive recrystallizations from
hexane.
(14) For a review on electrophilic amination, see: Erdik, E.; Ay, M.
Chem. Rev. 1989, 89, 1947.
(15) Reed, J . N.; Sniechus, V. Tetrahedron Lett. 1983, 24, 3795.

1
348 J . Org. Chem., Vol. 67, No. 4, 2002
Priego et al.
Ta ble 1. Dieth ylzin c Ad d ition to Ben za ld eh yd e
Sch em e 4
Ca ta lyzed by th e Liga n d s (RF c,RS)-4
5
entrya
ligand
t (h)
config
ee (%)b
yield (%)c
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4h
4h
4i
48
72
48
96
24
32
72
20
96
24
28
96
96
48
96
S
R
R
R
R
R
R
R
R
R
R
R
R
R
R
28
6
60
6
14
8
74
80
88
4
82
86
58
48
42
93
59
76
e
67
70
74
90
79
80
90
82
76
62
68
51
d
e
9
f
1
1
1
1
1
1
0
1
2
3
4
5
d
e
4i
4j
4k
4l
e
a
Reaction conditions: Et2Zn (200 mol %), ligand (5 mol %),
7
screening for asymmetric catalysis. Since the discovery
of Noyori et al.1 that aminoisoborneol derivatives are
very efficient N,O-bidentate chiral catalysts in this
reaction, an extraordinary structural variety of chiral
toluene, rt. b Determined by HPLC (Daicel Chiralcel OD). In pure
c
6
d
alcohol after flash chromatography. Reaction run at -20 °C.
e
Conversion yield. f Reaction run in the presence of Ti(O Pr) (120
i
4
mol %).
7
ligands have been reported to date, especially in the case
of compounds that possess amino alcohol frameworks.17
The results obtained in the addition of diethylzinc to
benzaldehyde in the presence of a catalytic amount of
ligands 4 are depicted in Table 1. The reactions were
performed under standard conditions: 5 mol % of ligand
-20 °C instead of room temperature, giving rise to (R)-5
in 88% and 86% ee’s, respectively (entries 9 and 12).
Other types of chiral sulfonamides, in particular C-2
symmetrical bissulfonamides derived from 1,2-cyclohex-
anediamine, had been reported as very efficient ligands
in the enantioselective titanium-catalyzed addition of
dialkylzinc reagents to aldehydes.18 With this kind of
4
, excess of diethylzinc (200 mol %) in toluene at room
temperature. Excepting the ligands having strong electron-
withdrawing substitution, ligands 4d and 4j (entries 4
and 13), the conversion was complete in 1-4 days,
showing that ferrocenes 4 act as catalysts in this reaction.
After final flash chromatography, acceptable to good
yields in alcohol 5 were obtained in all cases. With the
exception of the unsubstituted ligand 4a (entry 1), all
reactions led to the predominant formation of the alcohol
N,N-bidentate ligands the reaction is performed in the
i
presence of a titanium Lewis acid, usually Ti(O Pr)
4
, to
generate the key chiral titanium bis(sulfonamide) com-
plex. In our case the addition of diethylzinc to benzalde-
i
hyde catalyzed by ligand 4h and Ti(O Pr)
4
occurred in a
nearly nonenantioselective manner (4% ee, entry 10).
This drastic drop in the enantioselectivity could be
ascribed to the inability of the sulfoxide to act as a ligand
for the titanium atom, 4h behaving as an N-coordinating
titanium ligand rather than as a more rigid N,O-
bidentate ligand.19
To explore the scope of the optimal ligands 4h and 4i
as chiral catalysts in the addition of diethylzinc to
aromatic aldehydes, a variety of substrates with quite
different steric and electronic substitution on the aro-
matic ring were tested (Table 2). In all cases the reactions
occurred smoothly in toluene at room temperature and,
like in the addition to benzaldehyde, the corresponding
alcohol of (R) configuration was always obtained as the
major enantiomer20 (alcohols 6-11). As in previous cases,
the accurate determination of the ee’s was always
(R)-5, but with very different levels of enantiocontrol.
Although a low stereoselectivity was observed in the
presence of the amine and amide ligands (entries 2-6),
the sulfonamide series provided a significantly higher
and more homogeneous enantiocontrol, with ee’s ranging
from 42% to 82%. The best ligands were found to be the
p-tolylsulfonamide 4h (80% ee, entry 8) and the p-
methoxyphenylsulfonamide 4i (82% ee, entry 11). The use
of bulkier arylsulfonamides (ligands 4k and 4l, entries
1
4
4 and 15) or the electronically poor p-nitrosulfonamide
j (entry 13) had a detrimental effect in the enantiose-
lectivity. Interestingly, in the case of the optimal ligands
h and 4i the enantioselectivity was significantly en-
hanced by performing the reaction at lower temperatures,
4
(
16) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J . Am. Chem.
Soc. 1986, 108, 6071.
17) For very recent references, see: (a) Rasmussen, T.; Norrby, P.-
(18) For some very recent references, see for instance: (a) Balsells,
J .; Betancort, J . M.; Walsh, P. J . Angew. Chem., Int. Ed. 2000, 39,
3428. (b) Balsells, J ., Walsh, P. J . J . Am. Chem. Soc. 2000, 122, 3250.
(c) Prieto, O.; Ram o´ n, D. J .; Yus, M. Tetrahedron: Asymmetry 2000,
11, 1629. (d) Paquette, L. A.; Zhou, R. J . Org. Chem. 1999, 64, 7929.
(e) F u¨ rstner, A.; Muller, T. J . Am. Chem. Soc. 1999, 121, 7814. (f)
Arredondo, V. M.; Tian, S.; McDonald, F. E.; Marks, T. J . J . Am. Chem.
Soc. 1999, 121, 3633. (g) Lutz, C.; J ones, P.; Knochel, P. Synthesis 1999,
312.
(
O. J . Am. Chem. Soc. 2001, 123, 2464. (b) Zhao, G.; Li, X.-G.; Wang,
X.-R. Tetrahedron: Asymmetry 2001, 12, 399. (c) Pinho, P.; Andersson,
P. G. Tetrahedron 2001, 57, 1615. (d) Dimitrov, V.; Dobrikov, G.; Genov,
M. Tetrahedron: Asymmetry 2001, 12, 1323. (e) Panev, S.; Linden, A.;
Dimitrov, V. Tetrahedron: Asymmetry 2001, 12, 1313. (f) Nakamura,
Y.; Takeuchi, S.; Okumura, K.; Ohgo, Y. Tetrahedron 2001, 57, 5565.
(
1
g) Demyanovich, V. M.; Shishkina, I. N.; Zefirov, N. S. Chirality 2001,
3, 507.
(19) A similar very low ee was also observed using TMSCl as
additive.

2
-Amino-Substituted 1-Sulfinylferrocenes
J . Org. Chem., Vol. 67, No. 4, 2002 1349
Ta ble 2. Dieth ylzin c Ad d ition to Ar om a tic Ald eh yd es
Ca ta lyzed by th e Liga n d s 4h a n d 4i
Sch em e 5
t
prod.
ee
yieldc
(%)
entrya
Ar
ligand (h) (R) config (%)
1
2
3
4
5
6
7
8
9
0
1
2
p-NO2C6H4
p-NO2C6H4
p-MeOC6H4
p-MeOC6H4
p-MeC6H4
4h
4i
4h
4i
4h
4i
4h
4i
4h
4i
4h
4i
96
96
96
96
48
53
20
24
31
40
48
52
6
6
7
7
8
8
9
9
10
10
11
11
28
26
66
58
64
66
88
96
82
92
80
72
73e
e
75
65
61
d
d
d
d
e
e
86
72
71
78
73
79
76
74
p-MeC6H4
p-CO2MeC6H4
p-CO2MeC6H4
2-naphthyl
2-naphthyl
m-FC6H4
1
1
1
m-FC6H4
Ta ble 3. Dieth ylzin c Ad d ition to Ar om a tic Ald eh yd es
Ca ta lyzed by th e Liga n d s (RF c,RS)-4h a n d (SF c,SS)-13h
a
Reaction conditions: Et2Zn (200 mol %), ligand (5 mol %),
toluene, rt. Determined by HPLC (Daicel Chiralpak AD). In
pure alcohol after flash chromatography. Determined by HPLC
Daicel Chiralcel OD). Conversion yield.
b
c
d
e
(
established by HPLC (Daicel Chiralpak AD or Daicel
Chiralcel OD). For each aldehyde both ligands 4h and
entrya
Ar
ligand product ee (%)c yield (%)
c
4
i afforded rather similar enantioselections and, remark-
ably, with the exception of p-nitrobenzaldehyde (entries
and 2), which gave a disappointingly low ee, moderate
1
2
3
4
5
6
7
8
9
Ph
Ph
4h
13h
4h
13h
4h
13h
4h
13h
4h
13h
4h
13h
4h
13h
(R)-5
(S)-5
(R)-6
(S)-6
(R)-7
(S)-7
(R)-8
(S)-8
(R)-9
(S)-9
(R)-10
(S)-10
(R)-11
(S)-11
80
32
28
9
79
67
73
50
65
65
86
80
71
60
73
62
76
75
1
e
e
e
e
p-NO2C6H4
p-NO2C6H4
p-MeOC6H4
p-MeOC6H4
to relatively high enantioselectivities were obtained with
the rest of aldehydes. As the best results, ee’s higher than
d
d
d
d
66
39
64
48
88
69
82
53
80
33
9
0% (up to 96% ee) were observed in the addition of
diethylzinc to methyl 4-formylbenzoate and 2-naphthal-
dehyde in the presence of 4i (entries 8 and 10).
p-MeC H4
6
e
p-MeC6H4
p-CO2MeC6H4
p-CO2MeC6H4
2-naphthyl
2-naphthyl
m-FC6H4
Syn t h esis of E n a n t iop u r e p -Tolylsu lfin ylfer r o-
cen es. In our goal in developing a highly tunable family
of amino-substituted sulfinylferrocenes for enantioselec-
tive catalysis, once the effect of the substitution at the
nitrogen atom in enantiopure ferrocenes 4 was explored,
it was equally interesting to determine the influence of
the substitution at the sulfur atom in the asymmetric
1
1
0
1
12
13
1
4
m-FC6H4
a
Reaction conditions: Et2Zn (200 mol %), ligand (5 mol %),
b
toluene, rt, 1-4 days. Determined by HPLC (Daicel Chiralpak
AD). c In pure alcohol after flash chromatography. Determined
d
induction of the process. Thus, following a reported
e
procedure,1
0a,21
by HPLC (Daicel Chiralcel OD). Conversion yield.
(S) p-tolylsulfinylferrocene [(S)-12] was
,1R)
prepared by reaction of ferrocenyllithium with (S
S
°
C) and treated with tosyl azide. The resulting ferrocenyl
menthyl p-toluenesulfinate (40% yield). This sulfinylation
reaction was performed at -78 °C in order to avoid a
significant degree of racemization at the sulfur atom.
Under these conditions (S)-12 was obtained in 97% ee.
+
-
azide was in situ reduced with NaBH
2 S
4
(Bu
4
N I , THF-
H O) to furnish the aminoferrocene (SFc,S )-13a (67%
overall yield), whose very high optical purity was con-
firmed by conversion into its (S) Mosher’s amide (>99%
de). Tosylation of 13a under usual conditions (NaH,
2
A further recrystallization from n-hexane:Et O (1:3) gave
enantiomerically pure material (>99% ee, HPLC, Chiral-
cel OD). By applying the same one-pot method previously
developed for the tert-butylsulfinylferrocene deriva-
TsCl, CH
Scheme 5).
En a n tioselective Ad d ition s. The results obtained in
3 S
CN) led to the sulfonamide (SFc,S )-13h
(
tives, (S)-12 was ortho-deprotonated2 (LDA, THF, -78
1b
the addition of diethylzinc to several aromatic aldehydes
in the presence of a catalytic amount of the enantiopure
p-tolyl sulfoxide 13h are shown in Table 3. In all cases
satisfactory yields in alcohols 5-11 were obtained after
reasonable reaction times (1-4 days). For stereochemical
comparison purposes, the results obtained from the tert-
butyl sulfoxide 4h have been again included (odd entries).
(
20) The configurational assignment was established by comparison
of the sign of the optical rotation of the enriched enantiomeric mixtures
of the final products 6-11 with the reported values for the known
optically active compounds [all obtained (R) alcohols are dextrorota-
tory]. See, for instance: (a) Dai, W.-M.; Zhu, H.-J .; Hao, X.-J .
Tetrahedron: Asymmetry 2000, 11, 2315. (b) Shi, M.; Sui, W.-S.
Tetrahedron: Asymmetry 1999, 10, 3319. (c) Gibson, C. L. Tetrahe-
dron: Asymmetry 1999, 10, 1551. (d) J in, M.-J .; Ahn, S.-J .; Lee, K.-S.
Tetrahedron Lett. 1996, 37, 8767.
According to the fact that ligand (SFc,S
configuration to that of (RFc,R )-4h , the enantioselectivity
exerted by both ligands was also opposite [major forma-
tion of the (S)-alcohol in the case of (SFc,S )-13h ].
However, the most interesting conclusion of this com-
S
)-13h has opposite
(21) (a) Argouarch, G.; Samuel, O.; Riant, O.; Daran, J .-C.; Kagan,
S
H. B. Eur. J . Org. Chem. 2000, 2893. (b) Riant, O.; Argouarch, G.;
Guillaneux, D.; Samuel, O.; Kagan, H. B. J . Org. Chem. 1998, 63, 3511.
c) Rebi e` re, F.; Samuel, O.; Kagan, H. B. Tetrahedron Lett. 1990, 31,
S
(
3
121.

1
350 J . Org. Chem., Vol. 67, No. 4, 2002
Priego et al.
Sch em e 6
Ta ble 4. Dieth ylzin c Ad d ition to Ar om a tic Ald eh yd es
Ca ta lyzed by th e Liga n d s (RF c,RS)-4h , (RF c)-14, a n d
(
RF c)-15
t
prod.
ee
yieldc
(%)
entrya
Ar
ligand (h) (R) config (%)
b
d
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
4h
14
15
4h
14
15
4h
14
15
20
13
24
20
15
96
31
25
96
5
5
5
9
9
80
82
82
88
85
82
82
77
78
79
85
67
71
70
84
73
80
91
d
d
parative study was the very different performances of 4h
and 13h as chiral inductors: for every tested aldehyde
the enantioselectivity of the reaction was much lower
from the p-tolyl sulfoxide 13h (69% ee was the best
induction, entry 10) than from the tert-butyl sulfoxide 4h .
This fact could be due to the higher steric discrimination
imposed by the bulky tert-butyl group. As previously
indicated, a similar trend was observed by us in the
diastereoselective intramolecular Pauson-Khand reac-
tion of 1-sulfinyl-1,6-enynes2f and in the intermolecular
Heck arylations of â-sulfinyldihydrofurans.2g
p-CO2MeC6H4
p-CO2MeC6H4
p-CO2MeC6H4
2-naphthyl
2-naphthyl
2-naphthyl
e
e
9
10
10
10
a
Reaction conditions: Et2Zn (200 mol %), ligand (5 mol %),
toluene, rt. b Determined by HPLC (Daicel Chiralpak AD). In
pure alcohol after flash chromatography. Determined by HPLC
c
d
(
Daicel Chiralcel OD). e Conversion yield.
Regarding the stereochemical outcome, outstandingly,
F er r ocen es w ith On ly P la n a r Ch ir a lity. Because
most of the current methods of synthesis of chiral 1,2-
disubstituted ferrocenes require the presence of an ortho-
directing substituent with stereogenic centers, most of
the studies involving ferrocenes as chiral ligands deal
with compounds having both planar and central chiral-
both sulfide 14 and sulfone 15 showed a catalysis
efficiency very close to that displayed by the model
sulfoxide 4h . In all cases the reactions occurred with very
similar enantioselectivities, and in some cases 14 and 15
were even somewhat more effective than the sulfoxide
4
h (entries 2 and 3). These results clearly show that it
5
ity. However, for a more rational design of ferrocene
is the planar chirality of the ferrocene unit, and not the
stereogenic sulfur atom, that is the decisive structural
element involved in the asymmetric induction. In fact,
as can be deduced by comparing entries 1-3, 4-6, and
ligands the evaluation of the relative importance of each
chirality element is of great importance. Thus, Bolm et
al. have recently described22 that in a series of N,O-
bidentate ferrocenes both elements of chirality play a
significant role in the enantioselectivity of the addition
of dialkylzinc to aldehydes23 (chiral cooperativity).
From the sulfinylferrocene family 4, the synthesis of
compounds having exclusively planar chirality could be
readily achieved by straightforward oxidation/reduction
reactions of the sulfinyl group. Thus, the model ligand
7
-9, the contribution to the asymmetric induction due
to the chiral sulfinyl substitution in 4h appears to be
quite small.25 This surprisingly homogeneous enantio-
control observed in the sulfide-sulfoxide-sulfone series
of ligands (14, 4h , and 15), with quite different coordi-
nating, steric, and electronic properties around the sulfur
atom, leads us to speculate that these kinds of 1,2-
disubstituted ferrocenes behave as N-monocoordinating
ligands rather than more rigid bidentate N,O- or N,S-
chelating ligands, the bulky sulfur substituent likely
favoring a suitable steric discrimination in the coordina-
tion of diethylzinc with the nitrogen of the sulfonamide
moiety.
(
(
(
R
R
Fc,R
S
)-4h was reduced to the corresponding sulfide
Fc)-14 by treatment with NaI/(CF CO)
O in acetone24
Cl
2
3
2
89% yield), while its oxidation with MCPBA in CH
2
gave the corresponding sulfone (RFc)-15 (87% yield,
Scheme 6). The results obtained in the addition of
diethylzinc to several aldehydes in the presence of this
sulfide/sulfoxide/sulfone series of chiral ferrocene ligands
under the usual experimental conditions (toluene, rt) are
summarized in Table 4.
Con clu sion s
We have developed a practical three-step synthesis of
a novel family of chiral 1,2-heterosubstituted ferro-
cenes: 2-aminosubstituted 1-sulfinylferrocenes. These
compounds are prepared in enantiopure form by sulfi-
nylation of ferrocenyllithium with (R)-S-tert-butyl 1,1-
dimethylethanethiosulfinate or (S ,1R) menthyl p-tolu-
S
enesulfinate, ortho-diastereoselective electrophilic ami-
nation, and amine derivatization. Among all prepared
ligands, the (RFc,R ) tert-butylsulfinylferrocenyl sulfona-
S
mides 4h and 4i behaved as interesting chiral catalysts
in the enantioselective addition of diethylzinc to differ-
ently substituted aromatic aldehydes, affording the al-
cohol of (R) configuration with ee’s usually in the range
(
22) (a) Bolm, C.; Mu n˜ iz, K.; Seger, A.; Raabe, G.; G u¨ nther, K. J .
Org. Chem. 1998, 63, 7860. See, also: (b) Deng, W.-P.; You, S.-L.; Hou,
X.-L.; Dai, L.-X.; Yu, Y.-H.; Xia, W.; Sun, J . J . Am. Chem. Soc. 2001,
1
23, 6508. (c) Bolm, C.; Mu n˜ iz, K. Chem. Eur. J . 2000, 6, 2309.
23) For previous studies on ferrocenes as chiral ligands in the
(
addition of diethylzinc to aldehydes, see for instance: (a) Bastin, S.;
Agbossou-Niedercorn, F.; Brocard, J .; P e´ linski, L. Tetrahedron: Asym-
metry 2001, 12, 2399. (b) Zhang, W.; Yoshinaga, H.; Imai, Y.; Kida, T.;
Nakatsuji, Y.; Ikeda, I. Synlett 2000, 1512. (c) Bolm, C.; Mu n˜ iz, K.;
Hildebrand, J . P. Org. Lett. 1999, 1, 491. (d) Malfait, S.; P e´ linski, L.;
Brocard, J . Tetrahedron: Asymmetry 1998, 9, 2595. (e) Patti, A.;
Nicolosi, G.; Howell, J . A. S.; Humphries, K. Tetrahedron: Asymmetry
998, 9, 4381. (f) Bolm, C.; Mu n˜ iz Fern a´ ndez, K.; Seger, A.; Raabe, G.
Synlett 1997, 1051. (g) Dosa, P. I.; Ruble, J . C.; Fu, G. C. J . Org. Chem.
997, 62, 444. (h) Malfait, S.; P e´ linski, L.; Brocard, J . Tetrahedron:
1
1
Asymmetry 1996, 7, 653. (i) Watanabe, M. Synlett 1995, 1050. (j)
Watanabe, M. Tetrahedron Lett. 1995, 36, 8991. (k) Nicolosi, G.; Patti,
A.; Morrone, R.; Piattelli, M. Tetrahedron: Asymmetry 1994, 5, 1639.
(
l) Wally, H.; Widholm, M.; Weissensteiner, W.; Schl o¨ gl, K. Tetrahe-
dron: Asymmetry 1993, 4, 285.
24) Drabowicz, J .; Oae, S. Synthesis 1977, 404.
S
(25) As an additional example of this behavior, the sulfoxide (RFc,R )-
4i and its corresponding thioether gave also similar ee’s in the addition
of diethylzinc to benzaldehyde (86% and 74% ee, respectively).
(

2
6
-Amino-Substituted 1-Sulfinylferrocenes
J . Org. Chem., Vol. 67, No. 4, 2002 1351
5-96%. The comparison of the results of the sulfoxide
for 30 min, and MeI (0.92 g, 6.50 mmol) was added. The
reaction mixture was stirred for 12 h, and water was added.
The organic layer was separated, and the aqueous layer was
S
(RFc,R )-4h with those obtained from the corresponding
sulfide (RFc)-14 and sulfone (RFc)-15 revealed that the
planar chirality of the 1,2-disubstituted ferrocene is the
key structural element involved in the asymmetric
induction.
extracted with Et
2
O. The combined organic layers were dried
(
MgSO ) and filtered, and the solvent was evaporated. The
resulting mixture was purified by flash chromatography (ethyl
4
acetate-hexane 1:6) to afford the amine 4b (0.12 g, 57%). mp
1
1
33-134 °C; [R]20
D
) -540 (c ) 0.1, CHCl
3
); H NMR (200
MHz) δ 4.48 (s, 5H, Cp′-H), 4.18 (m, 2H, Cp-H), 4.06 (t, 1H, J
Exp er im en ta l Section
1
3
)
2.6 Hz, Cp-H), 2.73 (s, 6H, 2 Me), 1.17 (s, 9H, t-Bu);
C
Gen er a l Meth od s. Melting points are uncorrected. 1
NMR spectra were acquired at 200 or 300 MHz (indicated in
each case), and C NMR were acquired at 75 MHz. Chemical
shifts (δ) are reported in ppm relative to CDCl (7.26 and 77.0
H
NMR δ 113.8, 72.2, 70.6, 68.4, 63.5, 63.3, 57.4, 44.8, 24.3; MS
+
(EI) m/z 333 (M , 35), 317 (12), 277 (34), 259 (26), 246 (12),
1
3
149 (18), 139 (93), 138 (67), 97 (22), 84 (100), 69 (45), 57 (51);
Anal. Calcd for C H23FeNOS: C, 57.66; H, 6.96; N, 4.20; S,
3
1
6
ppm). Mass spectra (MS) was determined at an ionizing
voltage of 70 eV. All reactions were carried out in anhydrous
solvents. THF and diethyl ether were distilled from sodium-
9.62. Found: C, 57.27; H, 6.90; N, 4.09; S, 9.88.
Gen er a l P r oced u r e for th e Syn th esis of th e Am id es
4c-f: (R ,R )-2-(N-Acet yl)a m in o-1-(ter t-b u t ylsu lfin yl)-
F c
S
benzophenone under argon. CH
Flash column chromatography was performed using silica gel
Merck-60 (230-400 mesh). Et Zn (1 M) solution in hexane was
purchased from Sigma-Aldrich Co.
)-ter t-Bu tylsu lfin ylfer r ocen e
2
Cl
2
was distilled from P
2
O
5
.
F c S
fer r ocen e [(R ,R )-4c]. To a solution of amine 4a (149 mg,
0.49 mmol) in pyridine (1 mL), at 0 °C, was added Ac O (100
2
mg, 0.98 mmol). The reaction mixture was stirred for 2 h at 0
°C and then diluted with water. The pyridine was removed
under vacuum, and the aqueous layer was extracted with ethyl
2
9
,10
(
R
S
[(R)-1]. To a cold
solution (0 °C) of ferrocene (6.17 g, 33.18 mmol) in THF (50
mL) was added t-BuLi 1.7 M in pentane (17.0 mL, 28.75 mmol)
under argon atmosphere. The reaction mixture was stirred at
2 4
acetate. The combined organic layers were dried (Na SO ),
filtered, and evaporated. The resulting mixture was purified
by flash chromatography (ethyl acetate-hexane 1:3) to afford
2
0
0
°C for 2 h, and then a solution of (R)-S-tert-butyl 1,1-
amide 4c (166 mg, 98%). mp 138-139 °C; [R]
D
) -1119 (c )
1
1
1
dimethylethanethiosulfinate [(R)-2, 4.30 g, 22.12 mmol;
g80% ee] in THF (20 mL) was added. The reaction was
warmed to room temperature and then kept at this temper-
ature for 2 h. Brine was added, the organic layer was
3
0.08, CHCl ); H NMR (300 MHz) δ 9.06 (s, 1H, NH), 5.50 (m,
1H, Cp-H), 4.31 (s, 5H, Cp′-H), 4.17 (t, 1 H, J ) 2.5 Hz,
Cp-H), 4.08 (dd, 1H, J ) 2.4, 1.2 Hz, Cp-H), 2.01 (s, 3H, Me),
1.16 (s, 9H, t-Bu); 13C NMR δ 168.4, 97.0, 71.2, 70.1, 66.2, 65.4,
+
separated, and the aqueous layer was extracted with Et
2
O.
64.7, 57.0, 24.3, 22.7; MS (EI) m/z 347 (M , 70), 331 (11), 291
The combined organic layers were dried (MgSO ) and filtered,
4
(92), 273 (35), 232 (87), 208 (37), 165 (100), 121 (32), 57(60);
and the solvent was evaporated. The resulting mixture was
purified by flash chromatography (ethyl acetate-hexane 2:1)
to afford sulfoxide (R)-1 (2.52 g, 40%), which was recrystallized
from diethyl ether and hexane (1:1) to give pure sulfoxide (R)-1
Anal. Calcd for C16
9.23. Found: C, 55.45; H, 5.98; N, 3.90; S, 9.52.
(R F c ,R )-1-(t er t -B u t y ls u lfin y l)-2-[N -(t r iflu o r o a c e -
t yl)a m in o]fer r ocen e [(RF c,R )-4d ]. Acylating reagent:
(CF CO) O; eluent: ethyl acetate-hexane (1:6); yield: 74%;
mp 126-128 °C; [R]
2
H21FeNO S: C, 55.34; H, 6.10; N, 4.03; S,
S
S
[1.25 g, 99% ee, HPLC: Daicel Chiracel OD, i-PrOH/Hexane
3
2
2
0
1
2
/98, flow rate 0.70 mL/min, t : 19.3 min (R)-isomer and 24.3
R
D
3
) -1461 (c ) 0.08, CHCl ); H NMR
2
0
min (S)-isomer, detection at 254 nm]. mp 150-151 °C; [R]
D
(300 MHz) δ 10.35 (s, 1H, NH), 5.53 (dd, 1H, J ) 2.6, 1.4 Hz,
Cp-H), 4.39 (s, 5H, Cp′-H), 4.31 (t, 1H, J ) 2.8 Hz, Cp-H), 4.22
1
0a
20
)
)
-355 (c ) 0.5, CHCl
3
), 99% ee; Lit.
), 95% ee; H NMR (200 MHz) δ 4.68 (m, 1H,
[R]
D
) -339 (c
1
13
0.5, CHCl
3
(dd, 1H, J ) 2.6, 1.4 Hz, Cp-H), 1.20 (s, 9H, t-Bu); C NMR δ
Cp-H), 4.41 (m, 2H, Cp-H), 4.38 (s, 5H, Cp′-H), 4.35 (m, 1H,
Cp-H), 1.12 (s, 9H, t-Bu).
155.0, 154.4, 117.5, 113.7, 94.6, 71.7, 71.5, 67.0, 65.6, 65.3, 57.4,
+
22.6; MS (EI) m/z 401 (M , 36), 385 (3), 345 (72), 327 (100),
(
R
F c ,R
(RF c,R
.76 mmol) in THF (35 mL) was added n-BuLi (1.9 M) in
S
)-2-Am in o -1-(t er t -b u t y ls u lfin y l)fe r r o c e n e
)-4a ]. To a cold solution (0 °C) of sulfoxide 1 (1.38 g,
262 (11), 230 (14), 138 (34), 121 (20), 57 (52). Anal. Calcd for
[
4
S
C
16
H
18
F
3
FeNO
C, 48.11; H, 4.36; N, 3.49; S, 8.12.
(R F c ,R )-1 -(t e r t -B u t y l s u l fi n y l )-2 -[N -(t r i m e t h y l -
a cet yl)a m in o]fer r ocen e [(RF c,R )-4e]. Acylating reagent:
(t-BuCO) O; eluent: ethyl acetate-hexane (1:6); yield: 76%;
mp 109-111 °C; [R]
2
S: C, 47.90; H, 4.52; N, 3.49; S, 7.99. Found:
pentane (3.43 mL, 6.19 mmol) under argon. The mixture was
stirred at room temperature for 2 h, and then a solution of
tosyl azide (1.22 g, 6.19 mmol) was added at 0 °C. The resulting
solution was stirred at room temperature for 4 h, and a
S
S
2
2
0
1
D
3
) -754 (c ) 0.7, CHCl ); H NMR (300
+
-
solution of Bu
9 mmol) in H
was stirred at room temperature for 24 h, and then a second
solution of NaBH (0.36 g, 9.5 mmol) in H O (5 mL) was added.
After 24 h brine was added, the organic layer was separated,
and the aqueous layer was extracted with Et O. The combined
organic layers were dried (MgSO ) and filtered, and the solvent
was evaporated. The resulting mixture was purified by flash
Cl 1:3) to afford the
4
N I (0.70 g, 1.90 mmol) and NaBH
4
(0.72 g,
MHz) δ 9.45 (s, 1H, NH), 5.58 (m, 1H, Cp-H), 4.27 (s, 5H,
Cp′-H), 4.17 (t, 1 H, J ) 2.7 Hz, Cp-H), 4.07 (m, 1H, Cp-H),
1.21 (s, 9H, t-Bu); 13C NMR δ 177.3, 97.8, 71.1, 70.0, 66.2, 64.7,
1
2
O (10 mL) was added. The reaction mixture
+
4
2
57.0, 39.2, 27.3, 22.7; MS (EI) m/z 389 (M , 43), 333 (57), 268
(50), 232 (70), 165 (44), 121 (17). Anal. Calcd for C19
FeNO S: C, 58.60; H, 7.00; N,3.60; S, 8.20. Found: C, 58.49;
H, 7.24; N, 3.30; S, 7.83.
(RF c,R )-2-(N-Ben zoyl)a m in o-1-(ter t-bu tylsu lfin yl)fer -
r ocen e [(RF c,R )-4f]. Acylating reagent: (PhCO) O; eluent:
ethyl acetate-hexane (1:6); yield: 80%; mp 135-137 °C; [R]
27
H -
2
2
4
S
chromatography (ethyl acetate-CH
2
2
S
2
2
0
aminosulfoxide 4a [0.93 g, 64%, >98% ee, HPLC: Daicel
D
1
Chiralpak AS, i-PrOH/Hexane 5/95, flow rate 0.70 mL/min,
) -853 (c ) 0.9, CHCl ); H NMR (300 MHz) δ 10.24 (s, 1H,
3
t
R
9.9 min (S)-isomer and 12.2 min (R)-isomer, detection at
NH), 7.92 (m, 2H, Ar), 7.50 (m, 3H, Ar), 5.74 (m, 1H, Cp-H),
4.36 (s, 5H, Cp′-H), 4.28 (t, 1H, J ) 2.7 Hz, Cp-H), 4.17 (m,
1H, Cp-H), 1.21 (s, 9H, t-Bu); 13C NMR δ 164.7, 133.7, 131.6,
128.7, 126.9, 97.5, 71.3, 70.3, 66.4, 65.2, 64.8, 57.1, 22.7, 14.1;
1
2
54 nm]. mp 163-164 °C; [R]20
D
3
) -343 (c ) 0.1, CHCl ); H
NMR (200 MHz) δ 4.27 (s, 5H, Cp′-H), 4.09 (t, 1H, J ) 1.8 Hz,
Cp-H), 4.01 (m, 1H, Cp-H), 3.98 (t, 1H, J ) 2.5 Hz, Cp-H),
1
3
+
3
7
.64 (bs, 2H, NH
2
), 1.20 (s, 9H, t-Bu); C NMR δ 108.5, 70.7,
MS (EI) m/z 409 (M , 26), 393 (11), 353 (43), 335 (24), 288
+
0.0, 64.6, 64.2, 58.6, 57.0, 23.1; MS (EI) m/z 305 (M , 6), 249
(17), 232 (37), 165 (37), 105 (100), 77 (60). Anal. Calcd for
(8), 231 (26), 178 (5), 149 (51), 97 (28), 91 (13), 84 (44), 81 (40),
21 2
C H23FeNO S: C, 61.60; H, 5.70; N, 3.40; S, 7.80. Found: C,
7
5
4
1 (46), 69 (85), 57 (100). Anal. Calcd for C14
5.09; H, 6.27; N, 4.59; S, 10.50. Found: C, 54.69; H, 6.02; N,
.28; S, 10.61.
H
19FeNOS: C,
61.34; H, 5.85; N, 3.12; S, 7.33.
Gen er a l P r oced u r e for th e Syn th esis of Su lfon a m id es
4g-l: (RF c,R
l)a m in o]fer r ocen e [(RF c,R
(101 mg, 0.33 mmol) in CH CN (3 mL), at room temperature
S
)-1-(ter t-Bu tylsu lfin yl)-2-[N-(p-tolylsu lfon y-
(
R
Fc,R
S
)-1-(ter t-Bu tylsu lfin yl)-2-[N,N-(d im eth yl)a m in o]-
fer r ocen e [(RF c,R )-4b]. To a solution of amine 4a (0.20 g,
.65 mmol) in DMF (7 mL), at room temperature, NaH (0.10
g, 2.62 mmol) was added. The resulting solution was stirred
S
)-4h ]. To a solution of amine 4a
S
3
0
was added NaH (12 mg, 0.5 mmol). The reaction mixture was
stirred for 15 min, and TsCl (189 mg, 0.99 mmol) was added.

1
352 J . Org. Chem., Vol. 67, No. 4, 2002
Priego et al.
The resulting solution was stirred for 6 h, diluted with water,
and extracted with Et O. The combined organic extracts were
dried (Na SO ), filtered, and evaporated. The resulting mixture
was purified by flash chromatography (ethyl acetate-hexane
3.07 (s, 3H, Me), 1.22 (s, 9H, t-Bu); 13C NMR δ 99.1, 71.6, 68.4,
+
2
65.7, 64.9, 61.7, 57.1, 40.6, 22.8; MS (EI) m/z 383 (M , 45),
2
4
327 (66), 309 (59), 230 (100), 200 (46), 165 (45), 121(45). Anal.
Calcd for C15H21FeNO S : C, 47.00; H, 5.52; N, 3.65; S, 16.73.
3 2
Found: C, 47.29; H, 5.30; N, 3.41; S, 16.51.
1
:4) to afford sulfonamide 4h (103 mg, 68%): mp 154-155 °C;
2
0
1
[
1
R]
D
) -522 (c ) 0.1, CHCl
3
); H NMR (300 MHz) δ 8.57 (s,
(RF c)-1-(ter t-Bu t ylsu lfen yl)-2-[N-(p -t olylsu lfon yl)a m i-
n o]fer r ocen e [(RF c)-14]. To a solution of 4h (138 mg, 0.30
mmol) and NaI (22 mg, 0.90 mmol) in acetone (4 mL), at -40
H, NH), 7.86 (d, 2H, J ) 8.3 Hz, Ar), 7.32 (d, 2H, J ) 8.1 Hz,
Ar), 4.84 (dd, 1H, J ) 2.6, 1.4 Hz, Cp-H), 4.10 (bs, 7H, 5 Cp′-H
1
3
+
1
2
2 Cp-H), 2.42 (s, 3H, Me), 1.10 (s, 9H, t-Bu); C NMR δ
°C, (CF
mixture was stirred for 2 min, and saturated Na
saturated NaHCO was added. The organic layer was sepa-
rated, and the aqueous layer was extracted with CH Cl . The
combined organic layers were dried (Na SO ), filtered, and
3
CO)
2
O (252 mg, 1.2 mmol) was added. The reaction
43.8, 137.5, 129.7, 127.4, 99.0, 71.3, 68.2, 56.6, 64.8, 61.2, 57.0,
2
SO and
3
+
2.7, 21.5; MS (EI) m/z 459 (M , 61), 443 (36), 403 (99), 385
3
(71), 248 (60), 230 (67), 212 (100), 164 (62), 121 (44), 91 (48),
2
2
5
3
7 (54). Anal. Calcd for C21
.05; S, 13.96. Found: C, 54.70; H, 5.35; N, 2.99; S, 13.7.
)-1-(ter t-Bu tylsu lfin yl)-2-[N-(p-m eth oxyp h en yl-
su lfon yl)a m in o]fer r ocen e [(RF c,R )-4i]. Sulfonyl chloride:
p-MeOC SO Cl; eluent: ethyl acetate-hexane (1:4); yield:
4%; mp 160-161 °C; [R]
H
25FeNO
3
S
2
: C, 54.90; H, 5.49; N,
2
4
evaporated. The resulting mixture was purified by flash
(
R
F c,R
S
chromatography (ethyl acetate-hexane 1:6) to afford the
2
0
S
thioether 14 (118 mg, 89%): mp 103-104 °C; [R]
D
) -451 (c
1
6
H
4
2
) 0.08, CHCl ); H NMR (300 MHz) δ 7.82 (d, 2H, J ) 8.3 Hz,
3
2
0
1
7
D
) -476.3 (c ) 0.1, CHCl
3
); H
Ar), 7.30 (d, 2H, J ) 8.1 Hz, Ar), 6.30 (s, 1H, NH), 4.70 (dd,
1H, J ) 2.6, 1.4 Hz, Cp-H), 4.20 (dd, 1H, J ) 2.4, 1.4 Hz, Cp-
H), 4.06 (t, 1H, J ) 2.6 Hz, Cp-H), 3.95 (s, 5H, Cp′-H), 2.40 (s,
3H, Me), 1.06 (s, 9H, t-Bu); 13C NMR δ 143.9, 136.9, 129.6,
127.4, 98.7, 71.7, 70.7, 65.0, 64.7, 60.4, 46.6, 30.5, 21.5; MS
NMR (300 MHz) δ 8.51 (s, 1H, NH), 7.87 (d, 2H, J ) 8.9 Hz,
Ar), 6.98 (d, 2H, J ) 8.9 Hz, Ar), 4.83 (dd, 1H, J ) 2.6, 1.4 Hz,
Cp-H), 4.12 (s, 5H, Cp′-H), 4.10 (m, 1H, Cp-H), 4.07 (dd, 1H,
J ) 2.6, 1.4 Hz, Cp-H), 3.84 (s, 3H, MeO), 1.09 (s, 9H, t-Bu);
1
3
+
C NMR δ 163.0, 132.0, 129.4, 114.2, 99.0, 71.3, 68.1, 65.6,
(EI) m/z 443 (M , 72), 387 (74), 232 (100), 166 (57), 121 (19),
+
6
4
4.8, 62.0, 56.9, 55.6, 22.7; MS (EI) m/z 475 (M , 63), 459 (62),
19 (89), 403 (63), 401 (59), 272 (24), 248 (69), 232 (91), 228
2 2
91 (16), 57 (32). Anal. Calcd for C21H25FeNO S : C, 56.88; H,
5.68; N, 3.16; S, 14.46. Found: C, 57.28; H, 5.81; N, 3.02; S,
13.98.
25
(100), 166 (75), 121 (40), 77 (24), 57 (62). Anal. Calcd for C21H -
FeNO
4
S
2
: C, 53.05; H, 5.30; N, 2.95; S, 13.49. Found: C, 52.72;
(RF c)-1-(ter t-Bu t ylsu lfon yl)-2-[N-(p-t olylsu lfon yl)a m i-
n o]fer r ocen e [(RF c)-15]. To a solution of 4h (50 mg, 0.11
H, 4.98; N, 2.91; S, 13.19.
)-1-(t er t -Bu t ylsu lfin yl)-2-[N -(p -n it r op h e n yl-
su lfon yl)a m in o]fer r ocen e [(RF c,R )-4j]. Sulfonyl chloride:
p-NO SO Cl; eluent: ethyl acetate-hexane (1:4); yield:
7%; mp 181-182 °C; [R]
300 MHz) δ 8.96 (s, 1H, NH), 8.34 (d, 2H, J ) 8.5 Hz, Ar),
.11 (d, 2H, J ) 8.5 Hz, Ar), 4.96 (bs, 1H, Cp-H), 4.23 (s, 5H,
Cp′-H), 4.18 (bs, 1H, Cp-H), 4.11 (bs, 1H, Cp-H), 1.03 (s, 9H,
(
R
F c ,R
S
mmol) in CH
mmol) in CH
2
Cl
Cl
2
(1 mL) was added MCPBA (50%, 40 mg, 0.11
(0.5 mL). The mixture was stirred vigorously
S
2
2
2
C
6
H
4
2
at 25 °C. After 4 h saturated Na
aqueous NaHCO (2 mL) were added. The organic layer was
separated, and the aqueous layer was extracted with CH Cl
The combined organic layers were dried (Na SO ), and the
2 3
SO (2 mL) and saturated
2
0
1
5
(
8
D
) -776 (c ) 0.05, CHCl
3
); H NMR
3
2
2
.
2
4
solvent was evaporated. The resulting mixture was purified
1
3
t-Bu); C NMR δ 150.1, 146.2, 128.4, 124.3, 98.1, 71.7, 68.3,
by flash chromatography (ethyl acetate-hexane 1:5) to afford
+
20
6
4
6.1, 65.2, 62.5, 56.7, 22.5; MS (EI) m/z 490 (M , 47), 434 (90),
16 (53), 248 (35), 230 (100), 166 (53), 121 (38), 57 (74). Anal.
(R)-15 (45 mg, 87%): mp 141-143 °C; [R]
D
) -238 (c ) 0.1,-
1
3
CHCl ); H NMR (300 MHz) δ 7.83 (d, 2H, J ) 8.3 Hz, Ar),
Calcd for C20
Found: C, 48.75; H, 4.25; N, 5.55; S, 12.76.
)-1-(t er t -Bu t ylsu lfin yl)-2-[N -(2,4,6-t r im e t h yl-
p h en ylsu lfon yl)a m in o]fer r ocen e [(RF c,R )-4k ]. Sulfonyl
chloride: (CH SO Cl; eluent: ethyl acetate-hexane (1:
); yield: 45%; mp 186-187 °C; [R]
H
22FeN
2
O
5
S
2
: C, 48.99; H, 4.52; N, 5.71; S, 13.08.
7.33 (d, 2H, J ) 8.1 Hz, Ar), 4.95 (dd, 1H, J ) 2.6, 1.4 Hz,
Cp-H), 4.35 (dd, 1H, J ) 2.6, 1.4 Hz, Cp-H), 4.26 (t, 1H, J )
2.6 Hz, Cp-H), 4.19 (s, 5H, Cp′-H), 2.42 (s, 3H, Me), 1.17 (s,
9H, t-Bu); 13C NMR δ 144.2, 136.9, 129.8, 127.4, 97.6, 72.0,
(R F c,R
S
S
+
3
)
3
C
6
H
2
2
70.0, 66.8, 66.5, 63.3, 59.9, 23.0, 21.5; MS (EI) m/z 475 (M ,
2
0
2
D
) -440 (c ) 1, CHCl
3
);
72), 419 (20), 401 (19), 336 (28), 246 (42), 199 (25), 149 (30),
1
H NMR (300 MHz) δ 8.77 (s, 1H, NH), 7.03 (s, 2H, Ar), 4.57
122 (28), 91 (40), 69 (58), 57 (100). Anal. Calcd for C21
FeNO : C, 53.05; H, 5.26; N, 2.95; S, 1347. Found: C, 52.92;
H, 5.23; N, 2.84; S, 12.99.
(S )-p-Tolylsu lfin ylfer r ocen e
25
H -
(
t, 1H, J ) 2.0 Hz, Cp-H), 4.09 (m, 2H, Cp-H), 4.00 (s, 5H,
3 2
S
Cp′-H), 2.78 (s, 6H, 2 Me), 2.31 (s, 3H, Me), 1.21 (s, 9H, t-Bu);
1
3
10a ,21
C NMR δ 142.6, 139.3, 134.7, 132.2, 99.6, 70.8, 68.3, 65.5,
S
S
[(S )-12]. To a solution
+
6
4
4.4, 60.9, 57.4, 23.0, 22.9, 21.0; MS (EI) m/z 487 (M , 53),
of ferrocene (9.62 g, 51.7 mmol) in THF (85 mL), was added
at 0 °C, t-BuLi 1.7 M in pentane (26.0 mL, 44.2 mmol) under
argon. The solution was stirred at 0 °C for 2 h and then cooled
to -78 °C and transferred slowly to a cold (-78 °C) solution
of (S ,1R) menthyl p-toluenesulfinate (10.0 g, 34.0 mmol; g99%
S
ee) in THF (51 mL). The reaction was stirred at -78 °C for 2
h. Brine was added, the organic layer was separated, and the
31 (61), 248 (100), 240 (71), 230 (63), 165 (43), 119 (35), 57
(
36). Anal. Calcd for C23
S, 13.16. Found: C, 56.33; H, 5.90; N, 2.74; S, 12.99.
)-1-(ter t-Bu tylsu lfin yl)-2-[N-(1-n aph th alen esu lfo-
n yl)am in o]fer r ocen e [(RFc,R )-4l]. Sulfonyl chloride: 1-naph-
thalenesulfonyl chloride; eluent: ethyl acetate-hexane (1:2);
3 2
H29FeNO S : C, 56.67; H, 6.00; N, 2.87;
(
R
Fc,R
S
S
2
0
yield: 64%; mp 174-175 °C; [R]
D
) -329 (c ) 0.2, CHCl
3
);
aqueous layer was extracted with Et
2
O. The combined organic
1
H NMR (300 MHz) δ 9.05 (s, 1H, NH), 8.70 (dd, 1H, J ) 8.7,
layers were dried (MgSO ) and filtered, and the solvent was
4
0
)
8
.6 Hz, Ar), 8.46 (dd, 1H, J ) 7.5, 1.2 Hz, Ar), 8.12 (d, 1H, J
evaporated. The resulting mixture was purified by flash
chromatography (ethyl acetate-hexane 1:1) to afford sulfoxide
2
(S)-12 (4.4 g, 40%, 97% ee). Recrystallization from Et O and
hexane (3:1) gave pure sulfoxide (S)-12 [2.2 g, >99% ee,
HPLC: Daicel Chiracel OD, i-PrOH/hexane 10/90, flow rate
8.3 Hz, Ar), 7.95 (d, 1H, J ) 8.1 Hz, Ar), 7.80 (ddd, 1H, J )
.5, 7.0, 1.4 Hz, Ar), 7.64 (dd, 1H, J ) 8.1, 7.5 Hz, Ar), 7.62
(
ddd,1H, J ) 8.1, 7.0, 1.1 Hz, Ar), 4.59 (t, 1H, J ) 2.0 Hz,
Cp-H), 4.03 (s, 1H, Cp-H), 4.02 (s, 1H, Cp-H), 3.66 (s, 5H,
1
3
Cp′-H), 1.18 (s, 9H, t-Bu); C NMR δ 135.6, 134.6, 134.3, 129.7,
0.80 mL/min, t
R
: 13.7 min (R)-isomer and 15.1 min (S)-isomer,
2
0
1
6
4
29.1, 128.8, 128.5, 127.3, 124.7, 124.2, 111.4, 110.4, 99.2, 70.6,
8.1, 65.6, 64.6, 57.4, 22.9; MS (EI) m/z 495 (M , 45), 479 (41),
39 (62), 248 (100), 232 (62), 166 (55), 57 (48). Anal. Calcd for
detection at 254 nm]. mp 143-144 °C; [R]
D
) +303 (c ) 0.5,
+
10b
20
CHCl
3
), >99% ee; Lit. [R]
D
) +305 (c ) 0.5, CHCl ), 100%
3
1
ee; H NMR (200 MHz) δ 7.52 (d, 2H, J ) 8.3, Ar), 7.25 (d,
2H, J ) 8.4 Hz, Ar), 4.61 (dt, 1H, J ) 1.5, 2.3 Hz, Cp-H), 4.39-
4.35 (s+m, 7H, Cp-H+Cp′-H), 4.33-4.31 (m, 1H, Cp-H), 2.37
(s, 3H, Me).
C
24
H
25FeNO
C, 58.10; H, 5.06; N, 2.71; S, 12.57.
)-1-(ter t-Bu tylsu lfin yl)-2-[N-(m eth a n esu lfon yl)-
3 2
S : C, 58.18; H, 5.09; N, 2.83; S, 12.94. Found:
(RF c,R
S
a m in o]fer r ocen e [(RF c,R
S
)-4g]. Sulfonyl chloride: CH
3
SO
2
-
S S
(SF c,S )-2-Am in o-1-(p-tolylsu lfin yl)fer r ocen e [(SF c,S )-
Cl. In this case Et N (1.5 equiv) was used as base in CH
3
2
Cl
2
13a ]. To a cold solution of sulfoxide (S)-12 (1.0 g, 3.09 mmol)
in THF (20 mL), at -78 °C, was added LDA 0.3 M in THF (13
mL, 4.01 mmol) under argon. The mixture was stirred at -78
°C for 40 min, and then a solution of tosyl azide (1.20 g, 6.08
mmol) was added. The resulting solution was stirred at -78
as solvent; eluent: ethyl acetate-hexane (1:2); yield: 62%; mp
2
0
1
1
21-123 °C; [R]
D
3
) -637 (c ) 0.1, CHCl ); H NMR (300
MHz) δ 8.38 (s, 1H, NH), 4.88 (m, 1H, Cp-H), 4.39 (s, 5H,
Cp′-H), 4.19 (t, 1H, J ) 2.6 Hz, Cp-H), 4.16 (m, 1H, Cp-H),

2
-Amino-Substituted 1-Sulfinylferrocenes
J . Org. Chem., Vol. 67, No. 4, 2002 1353
°
C for 4 h. After being warmed to room temperature, and a
J ) 8.5 Hz, Ar), 7.11 (d, 2H, J ) 8.1 Hz, Ar), 4.92 (dd, 1H, J
) 2.6, 1.3 Hz, Cp-H), 4.26 (s, 5H, Cp′-H), 4.22 (dd, 1H, J )
2.6, 1.3 Hz, Cp-H), 4.11 (t, 1H, J ) 2.6 Hz, Cp-H), 2.38 (s, 3H,
Me), 2.35 (s, 3H, Me); 13C NMR δ 143.4, 141.9, 141.1, 136.8,
129.8, 129.5, 127.2, 124.2, 96.6, 75.8, 71.4, 65.8, 63.8, 63.7, 21.5,
+
-
solution of Bu
4
N I (0.46 g, 1.26 mmol) and NaBH
O (10 mL) was added. The reaction mixture
was stirred at room temperature for 24 h. After this time, a
second solution of NaBH (0.22 g, 6.0 mmol) in H O (5 mL)
4
(0.45 g,
1
2.0 mmol) in H
2
4
2
+
+
was added, and the reaction was stirred for additional 24 h.
Brine was added, the organic layer was separated, and the
21.4; MS (EI) m/z 493 (M , 10), 477 (M - O, 100), 348 (18),
322 (38), 212 (18), 166 (77), 121 (21), 91 (43). Anal. Calcd for
aqueous layer was extracted with Et
2
O. The combined organic
24 3 2
C H23FeNO S : C, 58.42; H, 4.70; N, 2.84; S, 13.00. Found:
layers were dried (MgSO ) and filtered, and the solvent was
4
C, 58.17; H, 4.71; N, 2.97; S, 13.04.
evaporated. The resulting mixture was purified by flash
chromatography (ethyl acetate-hexane 1:3) to afford the
Gen er a l P r oced u r e for th e En a n tioselective Ad d ition
of Dieth ylzin c to Ald eh yd es. To a solution of ligand 4i (7.6
mg, 0.02 mmol) in toluene (1 mL) at room temperature under
argon atmosphere was added a solution of diethylzinc (1 M)
in hexanes (0.80 mL, 0.80 mmol). After stirring for 30 min,
benzaldehyde (42 mg, 0.40 mmol) was added, and the reaction
mixture was stirred at room temperature for 2 days (the
disappearance of the aldehyde was monitored by TLC), the
mixture was quenched by addition of 5% HCl, and the mixture
2
0
aminosulfoxide 13a (0.69 g, 67%): mp 114-115 °C; [R]
D
)
1
+
453 (c ) 0.2, CHCl ); H NMR (300 MHz) δ 7.50 (d, 2H, J )
3
8
4
.5 Hz, Ar), 7.23 (d, 2H, J ) 8.1 Hz, Ar), 4.35 (s, 5H, Cp′-H),
.19 (dd, 1H, J ) 2.8, 1.2 Hz, Cp-H), 4.09 (dd, 1H, J ) 2.4, 1.2
Hz, Cp-H), 3.98 (dd, 1H, J ) 2.8, 2.4 Hz, Cp-H), 3.50 (bs, 2H,
1
3
NH ), 2.34 (s, 3H, Me); C NMR δ 142.6, 140.8, 129.7, 124.4,
2
+
1
5
1
6
4
06.3, 77.9, 70.6, 64.0, 63.5, 59.3, 21.3; MS (EI) m/z 339 (M ,
+
8), 323 (M -O, 100), 256 (19), 201 (19), 200 (26), 186 (30),
was extracted with Et
washed with brine, dried (MgSO
The resulting mixture was purified by flash chromatography
2
O. The combined organic layers were
66 (20), 121 (38), 91 (21). Anal. Calcd for C17
H
17FeNOS: C,
4
), filtered, and evaporated.
0.19; H, 5.05; N, 4.13; S, 9.45. Found: C, 60.11; H, 4.98; N,
.27; S, 9.23.
2
0
(ethyl acetate-hexane 1:6) to afford (R)-5 [44 mg, 82%, [R]
) +39 (c ) 4.6,CHCl ), 82% ee, HPLC: Daicel Chiracel OD,
i-PrOH/hexane 5/95, flow rate 1 mL/min, t : 14.8 min (R)-
D
(
S
Fc,S
S
)-1-(p-Tolylsu lfin yl)-2-[N-(p-tolylsu lfon yl)a m in o]-
fer r ocen e [(SF c,S )-13h ]. To a solution of amine 13a (100.0
mg, 0.29 mmol) in CH CN (3 mL), at 0 °C, was added NaH
8.4 mg, 0.35 mmol). The reaction mixture was stirred for 15
min at room temperature, and a solution of TsCl (110.6 mg,
3
S
R
3
isomer and 16.3 min (S)-isomer, detection at 254 nm].
The same procedure (reaction times of 1-4 days) was
(
2
0
applied to the preparation of the known alcohols 6-11.
0
3
.58 mmol) was added. The resulting solution was stirred for
h, diluted with water, and extracted with Et O. The
), filtered, and
Ack n ow led gm en t. Financial support of this work
by the Ministerio de Ciencia y Tecnolog ´ı a (BQU2000-
0226) is gratefully acknowledged. J .P. and O.G.M. thank
the Ministerio de Educaci o´ n y Cultura for a predoctoral
fellowship.
2
combined organic extracts were dried (MgSO
4
evaporated. The resulting mixture was purified by flash
chromatography (ethyl acetate-hexane 1:1) to afford sulfona-
2
0
mide 13h (71 mg, 50%): mp 140-141 °C; [R]
D
) +494 (c )
1
0
2
.2, CHCl
3
); H NMR (300 MHz) δ 8.16 (s, 1H, NH), 7.62 (d,
H, J ) 8.3 Hz, Ar), 7.25 (d, 2H, J ) 8.2 Hz, Ar), 7.15 (d, 2H,
J O016271P