Salicylaldehyde Schiff bases derived from 2-ferrocenyl-2-amino alcohols. Part 1: New chiral ligands for the titanium-catalyzed enantioselective cyanation of aldehydes

Article abstract of DOI:10.1016/j.tetasy.2006.03.016

The condensation of a set of diversely substituted (S)-2-amino-2-ferrocenyl ethanol derivatives 1a-e with the salicylaldehydes 5A-C resulted in the generation of a small library of new chiral Schiff base-ligands, whose titanium isopropoxide complexes have

Full text of DOI:10.1016/j.tetasy.2006.03.016

Tetrahedron: Asymmetry 17 (2006) 1089–1103
Salicylaldehyde Schiff bases derived from 2-ferrocenyl-2-amino
alcohols. Part 1: New chiral ligands for the
titanium-catalyzed enantioselective cyanation of aldehydes
a
Rosa M Moreno, Malgorzata Rosol and Albert Moyano*
Unitat de Recerca en S ı´ ntesi Asim e` trica, Departament de Qu ı´ mica Org a` nica, Universitat de Barcelona,
Facultat de Qu ı´ mica, C. Mart ı´ i Franqu e` s 1-11, 08028 Barcelona, Spain
Received 6 March 2006; accepted 15 March 2006
Available online 27 April 2006
We dedicate this paper to the memory of Professor Marcial Moreno-Ma n˜ as
Abstract—The condensation of a set of diversely substituted (S)-2-amino-2-ferrocenyl ethanol derivatives 1a–e with the salicylaldehydes
5
A–C resulted in the generation of a small library of new chiral Schiff base-ligands, whose titanium isopropoxide complexes have been
tested as catalysts in the asymmetric addition of trimethylsilyl cyanide to aldehydes. The enantioselectivity of the reaction is strongly
influenced (a) by the substitution pattern of the 2-amino-2-ferrocenyl ethanol moiety, and (b) by the nature of the C3 substituent in
0
the salicylaldehyde. Computational modelling of the intermediate transition state complexes (based on the Schiff base, benzaldehyde,
isopropoxide and cyanide bonded to titanium) show that the experimental results can be accommodated by a careful analysis of the steric
interactions between the 2-aminoethanol and salicylaldehyde moieties, and the metal-coordinated aldehyde.
ꢀ
2006 Elsevier Ltd. All rights reserved.
1. Introduction
Rp
salicylaldehyde
moiety
Chiral Schiff bases derived from salicylaldehydes and from
-amino alcohols constitute a class of ‘privileged’ ligands1
Rα
R1
R2
R3
2
Ro
whose metal complexes are enantioselective catalysts for
important asymmetric processes, such as enantioselective
N
OH
amino alcohol
moiety
2
3
Michael reactions, silylcyanation of aldehydes, addition
OH
4
5
R4
of diketene and of diethylzinc to aldehydes, oxidation
of sulfides, arylation of epoxides, hetero-Diels–Alder
and hetero-ene reactions and cyclopropanation of olefins.
6
7
Figure 1. General structure of chiral salicylaldehyde Schiff base-ligands.
8
9
Although the modular nature of these ligands offers several
possibilities for structural modification (Fig. 1), structure/
9
d,10
enantioselectivity studies
aiming to optimize them have
On the other hand, work from our laboratory resulted in
the development of a general, stereoselective and enantio-
divergent synthesis of 2-amino-2-ferrocenylalkanols. Chiral
auxiliaries and ligands derived from this new type of metal-
locene amino alcohols have been shown to be useful stereo-
been mainly focused on the substituents of the salicylalde-
hyde moiety, and a relatively limited set of 2-amino alco-
hols, most of them derived from a-amino acids, has been
used for their preparation (Fig. 2). In particular, as can
be seen in Figure 2, the effect of the simultaneous presence
11
chemical controllers in a variety of carbon–carbon and
carbon–heteroatom bond-forming processes.1
2,13
More-
of two substituents at C does not appear to have been
2
investigated.
over, we have recently demonstrated that the properties
of these chiral auxiliaries or ligands can be efficiently mod-
ulated by the introduction of substituents in the 2-amino-2-
ferrocenylethanol moiety that dictate the conformational
*
Corresponding author. Tel.: +34 93 4021245; fax: +34 93 3397878;
e-mail: amoyano@ub.edu
1
3
preferences of the ferrocenyl group.
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.03.016

a
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R. M Moreno et al. / Tetrahedron: Asymmetry 17 (2006) 1089–1103
monosubstituted 2-amino alcohols
H2N
OH
R = Me, CH2Ph,
Pr, Bu, Ph
i
t
R
H2N
OH
disubstituted 2-amino alcohols
Me
H2N
R
OH
R = Me, Ph
trisubstituted 2-amino alcohols
Ph
H2N
R
OH
Ph
H2N
OH
i
R = Me, Pr, Ph
iPr
Ph
Ph
H2N
R
OH
Ar
H2N
OH
R = Me, CH2Ph
Ar
tBu
Ar =
OAlk
Figure 2. Chiral 2-amino alcohols used in the construction of salicylaldehyde Schiff base-ligands.
In light of these precedents, we decided to prepare a collec-
tion of salicylaldehyde Schiff base-ligands derived from 2-
amino-2-ferrocenylethanols with different degrees of substi-
tution both at the C and the C positions, in order to
investigate the catalytic efficiency of their titanium alkoxide
complexes in enantioselective additions to aldehydes. We
herein report the first results of this study, showing that
these novel chiral complexes are able to catalyze the enan-
tioselective cyanation of aldehydes. The application of
these complexes to the asymmetric addition of diketene
to aldehydes is discussed in the following paper in this
issue.
methyl substituents, and the phenyl-substituted compound
1e, as the chiral amino alcohols to be incorporated into the
salicylaldehyde Schiff base-ligands (Fig. 3).
1
2
1
1a
The preparation of amino alcohols 1a (99:1 er), 1c (96:4
1
4
13
er), and 1d (97:3 er) has been reported elsewhere, mean-
ing that we shall only describe in some detail our
approaches to 1b and to 1e. The starting product for the
synthesis of 1b (Scheme 1) is (1S,2R)-1-ferrocenylpro-
pane-1,2-diol 2, which can be obtained with a 98:2 er by
the Sharpless asymmetric dihydroxylation of (E)-1-prop-
1
5
1-enylferrocene (E)-(3). Although this compound has
been prepared in high diastereomeric purity by means of
the Schlosser–Christmann modification of the Wittig reac-
1
6
2
. Results and discussion
tion, we found that it was much more convenient to use
the ca. 4:1 (E)/(Z) mixture resulting from the addition of
ethylmagnesium bromide to ferrocenecarbaldehyde and
subsequent alumina-promoted dehydration of the inter-
2
2
.1. Synthesis of salicylaldehyde Schiff bases derived from
-amino-2-ferrocenylethanols
1
7
mediate alcohol. As foreseen, the asymmetric dihydroxyla-
At the outset of our studies, we selected the ferrocene deriv-
tion of this mixture using (DHQD) PYR as the chiral
2
atives 1a–1d, differing in the number and position of the
ligand afforded, after chromatographic purification, the
NH2
OH
NH2
OH
NH2
OH
NH2
OH
Fe
Fe
Fe Me
Fe
Me
Me Me
1a
1b
1c
1d
NH2
OH
Fe
Ph
1
e
Figure 3. Chiral 2-amino-2-ferrocenylethanol derivatives used in this work.

a
R. M Moreno et al. / Tetrahedron: Asymmetry 17 (2006) 1089–1103
1091
H
Me
Me
H
O
H
OH
+
Fe
i
Fe
H
ii
Fe
OH
Fe
H
Me
3
2
(Z)-3
iii, iv
NH2
OH
N3
Fe
Fe
OAc
v
Me
Me
1b
4
Scheme 1. Reagents and conditions: (i) EtMgBr (1.5 equiv), THF, 0 ꢁC to rt, 30 min; Al
mixture). (ii) K [Fe(CN) ] (3 equiv), K CO (3 equiv), (DHQD) PYR (0.05 equiv), K OsO
98:2 er), 19% (Z)-3. (iii) Ac O (25 equiv), pyridine, rt, 12 h, 100%. (iv) NaN (10.8 equiv), 1:3 methanol/water, 60 ꢁC, 4.5 h, 70%. (v) LiAlH
THF, 0 ꢁC to rt, 40 min, 100%.
2
O
3
, toluene, Dean–Stark, reflux, 5 h, 85% (ca. 4:1 (E)/(Z)
(OH) (0.05 equiv), 1:1 acetonitrile/water, rt, 30 min, 81% 2
(3.0 equiv),
3
6
2
3
2
2
2
4
(
2
3
4
desired diol 2 in high diastereo- and enantiomeric purity,
together with the unreacted (Z)-isomer of 3. After conver-
sion to its diacetate, 2 was treated with sodium azide in
aqueous methanol, to give, in 70% yield, the expected
ethanol led to the stable chiral Schiff bases 6aA–cC in good
yields. In the case of 1e, the reaction with 5B proceeded
in a quantitative yield, according to TLC. However, the
resulting Schiff base 6eB was extremely sensitive and
decomposed upon attempted isolation. For comparison,
Oguni’s ligand 7 was prepared in a similar way from
(R)-phenylglycinol and 3-tert-butyl-2-hydroxybenzalde-
hyde 5B.
(
1S,2R)-azidoacetate 4 with complete regioselectivity and
1
8
3b
without any loss of stereochemical purity. Finally, reduc-
tion of 4 with excess lithium aluminium hydride produced
the amino alcohol 1b in essentially quantitative yield.
On the other hand, enantiopure (99.5:0.5 er) 1e was readily
accessed via the catalytic hydrogenation of (1R,2S)-2-
Since reduced Schiff base-ligands have recently been shown
1
9
to be active in catalytic asymmetric Strecker reactions
and in the enantioselective cyanosilylation of aldehydes,
1
1b
20
azido-2-ferrocenyl-1-phenylethanol
(Scheme 2).
compounds 6dA, 6aB and 6bB were treated with sodium
borohydride in the presence of cerium(III) chloride hepta-
hydrate (Luche’s reagent) to afford the corresponding
N3
NH2
2
1
22
Fe
OH
Fe
OH
N-salicyl-b-amino alcohols 8dA, 8aB and 8bB (Scheme 3).
i
Ph
Ph
2.2. Asymmetric catalytic trimethylsilylcyanation of
aldehydes
1e
Scheme 2. Reagents and conditions: (i) PtO
2
(cat.), H
2
(balloon), EtOH,
rt, 12 h, 100%.
The enantioselective cyanation of carbonyl and imino
groups ranks amongst the most thoroughly studied pro-
cesses in asymmetric catalysis. Due to the synthetic
2
3
The condensation of amino alcohols 1a–d with salicylalde-
hyde derivatives 5A–C (Fig. 4 and Table 1) in absolute
importance of optically active a-cyanohydrins and a-
H
5
5
A
B
O
O
OH
R2
H
H
1a-e
H
H
tBu
tBu
R1
OH
Me
N
N
OH
OH
OH
OH
R5
Fe R3
H
R4
6aA-cC
7
5
C
O
OH
Figure 4. Salicylaldehyde Schiff bases prepared in this work.

a
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R. M Moreno et al. / Tetrahedron: Asymmetry 17 (2006) 1089–1103
Table 1. Synthesis of Schiff base-ligands from ferrocenyl amino alcohols
H
R2
0.2 equivs.
Me
tBu
N
OH
H
(
S) OH
R1
Me
N
OH
OH
i
0
.2 equivs. Ti(O Pr)4
CH2Cl2, -80 ºC
OSiMe3
CN
O
Me3SiCN
Fe
R3
R
+
R
R5
H
R4
6
0:40-98:2 er (R)
a
R
1
R
2
R
3
R
4
R
5
Ligand
Yield (%)
R = aryl, alkenyl, alkyl
H
H
H
H
H
H
H
H
Me
H
H
H
Me
H
H
H
H
6aA
6bA
6dA
6aB
6bB
6cB
6dB
6aC
6bC
6cC
77
92
90
89
99
75
93
63
88
87
Me
Me
H
Me
H
Me
H
Me
H
Scheme 4. Enantioselective trimethylsilylcyanation of aldehydes catalyzed
by a chiral Schiff base–titanium isopropoxide complex, according to Oguni
(Refs. 3a,b).
H
H
H
H
H
H
H
H
Me
H
t
Bu
t
t
t
Bu
Bu
Bu
at the 3-position of the salicylaldehyde moiety] was
rationalized in terms of a hexacoordinated, aldehyde-
H
1
1
1
-Adamantyl
-Adamantyl
-Adamantyl
Me
Me
Me
H
H
Me
3
b
bound titanium complex.
Subsequently, Yaozhong et al.26 described the use of Schiff
bases derived from 2-amino-1,2-diphenylethanol in the
a
Yield of product isolated after chromatographic purification. Reaction
conditions: 1.0 mmol amino alcohol 1a–d, 0.98 mmol salicylaldehyde
2
0
5A–C, 5 ml absolute EtOH, rt (5A,5B) or 50 ꢁC (5C).
same process, and, recently, Feng has found that the ami-
no alcohols obtained by the reduction of these Schiff bases
also lead to efficient catalytic systems for enantioselective
aldehyde cyanation. On the other hand, Somanathan and
aminonitriles, research in this topic continues unabated.24
One of the earliest non-enzymatic methods for practical
enantioselective cyanohydrin synthesis is due to Oguni,
who in 1991 reported that chiral Schiff base complexes
of titanium alkoxides were effective catalysts for the enan-
tioselective addition of trimethylsilyl cyanide to aldehydes.
1
0
Walsh have studied the effect of steric hindrance in the
titanium alkoxide complexes of Schiff bases derived from
cis-1,2-aminoindanol, showing that the presence of bulky
substituents at the 3-position of the salicylaldehyde moiety,
necessary to achieve good enantioselectivities, inhibits the
3
a
3
b,25
The screening of a variety of Schiff bases
revealed that
formation of catalytically inactive L Ti species.
2
the best ligand was that derived from 3-tert-butyl-2-
hydroxybenzaldehyde 5B and (S)-valinol. In the presence
of 20 mol % of the titanium di(isopropoxide) complex de-
rived from this ligand, trimethylsilyl cyanide added (at
We selected the asymmetric addition of trimethylsilylcya-
nide to benzaldehyde as the benchmark reaction to test
the relative catalytic efficiency of our ferrocenyl imino alco-
hols (Table 2).
ꢀ
80 ꢁC in dichloromethane solution) to a variety of alde-
hydes, affording the (R)-cyanohydrins in good yields and,
in several instances, with excellent enantiomeric purities
Initially, we proceeded to optimize the reaction conditions
with the phenylglycinol-derived Schiff base 7 (entry 1 of Ta-
ble 3). To our satisfaction, we found that by performing the
process at ꢀ60 ꢁC, the addition was complete after 40 h,
(
Scheme 4). When the Schiff base derived from 2-hydroxy-
benzaldehyde 5A and (S)-valinol, lacking the 3-tert-butyl
substituent, was used as a ligand, the (S)-configured cyano-
hydrin of benzaldehyde was isolated in only 61:39 er, in
contrast to the 93:7 er obtained with the ligand derived
from 5B. The stereochemical outcome of the reaction
2
7
affording the benzaldehyde cyanohydrin (S)-9 in 80%
yield and in 75:25 er (determined by chiral GC analysis
of the corresponding acetate). It is worth noting that with
3
b,25
[
highly predominant addition to the si face of the aldehyde
the same ligand but at ꢀ80 ꢁC, Oguni
had reported a
with (S)-configured Schiff bases having bulky substituents
40% yield (with a 70:30 er) for this compound. Under these
R2
R2
H
R1
R1
N
OH
OH
R5
NH OH
i
OH
Fe R3
Fe R3
R5
R4
R4
6
6
6
dA, R1,R2,R3=H, R4,R5=Me
8dA, R1,R2,R3=H, R4,R5=Me
t
t
aB, R1= Bu, R2,R3,R4,R5=H
8aB, R1= Bu, R2,R3,R4,R5=H
t
t
bB, R1= Bu, R2,R3,R4=H, R5=Me
8bB, R1= Bu, R2,R3,R4=H, R5=Me
Scheme 3. Reagents and conditions: (i) NaBH
4
(2 equiv), CeCl
3
Æ7H
2
O (1 equiv), methanol, ꢀ78 ꢁC to rt, 75–90 min; 77% (8dA), 48% (8aB), 73% (8bB).

a
R. M Moreno et al. / Tetrahedron: Asymmetry 17 (2006) 1089–1103
1093
Table 2. Asymmetric addition of trimethylsilyl cyanide to benzaldehyde catalyzed by chiral Schiff base–titanium isopropoxide complexes
OH
O
H
i
0
.2 equivs ligand, Ti(O Pr)4
CN
*
+
Me3SiCN
o
CH2Cl2, -60 C, 64-68 h
1M HCl
9
a
b
c
Entry
Ligand
Yield (%)
Er
Configuration
d
1
2
3
4
5
6
7
8
9
7
80
75:25
59:41
85:15
80:20
93:7
46:54
62:38
75:25
76:24
58:42
(S)
(S)
(S)
(S)
(S)
(R)
(S)
(S)
(S)
(S)
6dA
6aB
6bB
6cB
6dB
85
83
72
91
e
85
f
6eB
6aC
6cC
8aB
27
32
65
60
10
a
b
c
d
e
f
Yield of isolated product 10 after chromatographic purification.
By GC (b-DEX 120 column) of the corresponding acetate.
By comparison of the sign of specific rotation values of the acetate with that in the literature.
27
4
4
0 h of stirring.
days of stirring.
Generated in situ by condensation of 5B with 1e before the addition of titanium tetra(isopropoxide).
Table 3. Enantioselective addition of trimethylsilyl cyanide to aldehydes catalyzed by Schiff base (6aB, 6bB)–titanium isopropoxide complexes
i
OH
CN
O
H
0.2 equivs ligand, Ti(O Pr)4
+
Me3SiCN
R
o
CH2Cl2, -60 C
R
1
M HCl
(
S)
a
b
c
Entry
1
R
Ligand
Time (h)
70
Yield (%)
60
Er
Configuration
OMe
OMe
6aB
80:20
77:23
(S)
2
6bB
62
85
(S)
MeO
MeO
3
4
5
6aB
6aB
6aB
70
63
64
85
47
69
71:29
62:38
82:18
(S)
(S)
(S)
Me
Me
6
7
8
9
6bB
6aB
6aB
6aB
6aB
62
64
64
41
41
55
77
70
76
63
79:21
57:43
73:27
72:28
81:19
(S)
(S)
(S)
(S)
(S)
NC
F
Me
1
0
Me
a
b
c
Yield of isolated product after chromatographic purification.
By F NMR analysis of their MTPA esters.
By comparison of the sign of optical rotation values with those in the literature.
19
3b,29,30

a
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R. M Moreno et al. / Tetrahedron: Asymmetry 17 (2006) 1089–1103
conditions, preformed dichloromethane solutions of the
titanium di(isopropoxide) complexes of our ferrocene-de-
rived Schiff bases were stirred at ꢀ60 ꢁC with benzaldehyde
cyanation of benzaldehyde, affording benzaldehyde cyano-
hydrin (S)-9 with moderate to good enantioselectivity.
(
5 M equiv) and cyanotrimethylsilane (10 M equiv) for 64–
We also examined the catalytic performance of the tita-
nium alkoxide complexes derived from Schiff bases 6aB
and 6bB in the enantioselective addition of trimethylsilyl
cyanide to a set of representative aromatic and a,b-unsatu-
rated aldehydes. The results of this study are summarized
in Table 3.
6
8 h. After acidic hydrolysis, benzaldehyde cyanohydrin 9
was isolated in variable yields and enantiomeric purities.
The formation of the titanium complexes was readily evi-
denced in each case by a colour change of the solution from
yellow to red upon addition of titanium tetra(isopropox-
ide) to the Schiff base solution. Moreover, when a
deuterated chloroform solution of 6bA was treated with
equimolar amounts of titanium tetra(isopropoxide) (final
As shown in Table 3, most aldehydes were cyanated in
good yields (60–85%), and with enantiomeric purities that
were strongly dependent upon the structure of the sub-
strate. As for the stereochemistry of the products, the abso-
lute configuration of the cyanohydrins was in all instances
(S), as determined by the comparison of the sign of the spe-
cific rotation values with those reported in the literature
(see Experimental). In accordance to the findings of Ogu-
1
13
concentration 0.1 M), both the H and the C NMR spec-
tra of the resulting mixture indicated that a 1:1 ligand–tita-
nium complex was the major species present in solution
(
together with isopropyl alcohol).3b,28 As expected,3,10,25
ligands 6aA, 6bA and 6dA, derived from the unsubstituted
salicylaldehyde 5A, catalyzed the reaction with very low
enantioselectivity. The best results were obtained in the
case of 6dA that gave (S)-9 in 85% yield and with a 59:41
er (entry 2). We next turned our attention to the 3-tert-
butyl-substituted imines 6aB–eB. The complex derived from
3
b,25
ni,
the smallest enantioselectivity corresponded to the
strongly electron-deficient 4-cyanobenzaldehyde (entry 7),
while higher enantiomeric purities were recorded for p-tolu-
aldehyde (entries 5 and 6) and for p-fluorobenzaldehyde
(entry 8). Some interesting trends were observed in the silyl-
cyanation of the o-, m- and p-isomers of anisaldehyde (en-
6
aB (entry 3) afforded (S)-9 with an 86:14 er. The enantio-
meric purity of the product was not improved by the pres-
3
b,25
10b
ence of a methyl substituent at C in the amino alcohol
tries 1–4). Both Oguni
and Walsh had reported that
1
moiety (ligand 6bB, entry 4). When positioned at C (ligand
in this case, the enantioselectivity of the reaction markedly
decreased in the order p > m > o, and only a 60:40 er was
obtained for o-anisaldehyde with Walsh’s cis-1,2-amino-
2
6
cB, entry 5), the methyl group did not change the enantio-
facial selectivity of the addition, and a substantial increase
in both the yield and in the enantioselectivity of the reac-
tion was observed, since (S)-9 was obtained in excellent
yield (91%) and with a 93:7 er (97:3 er when taking into ac-
count the enantiomeric purity of 6cB). The best conditions
found by Oguni for benzaldehyde, using the 5B-(S)-valinol
Schiff base at ꢀ80 ꢁC, afforded (R)-9 in 67% yield and with
1
0b
indanol-derived ligand.
Remarkably enough, the oppo-
site behaviour was observed with our (S)-2-amino-2-
ferrocenylethanol-derived ligand 6aB that afforded (S)-2-
3
1
hydroxy-2-(2-methoxyphenyl)acetonitrile in 80:20 er. On
the other hand, and with the same ligand, the tri-
methylsilylcyanation of trans-crotonaldehyde (entry 9) and
of methacrolein (entry 10) took place with 73:27 and with
80:20 er, respectively.
3
a 93:7 er. Schiff base 6cB is, therefore, a very efficient
ligand for the titanium-catalyzed asymmetric cyanation of
benzaldehyde. The presence of a gem-dimethyl moiety
(
ligand 6dB, entry 6) or of a phenyl substituent (ligand 6eB,
2.3. Mechanistic considerations. Molecular modelling of
intermediate complexes
entry 7) at C diminished both the rate and enantioselectiv-
1
ity of the reaction. In the case of 6dB, the major enantio-
mer (54:46 er) of the cyanohydrin product 9 had an (R)-
configuration. In accordance with the findings of Somana-
than and Walsh, replacement of tert-butyl by adamantyl
in the salicylaldehyde moiety resulted in the generation of
less efficient catalysts (ligand 6aC, entry 8; ligand 6cC,
entry 9), as it was the case with the reduced Schiff base-ligand
In 1993, Oguni3b proposed that the catalytic asymmetric
cyanation of aldehydes was initiated by the coordination
of the aldehyde to the initially formed, coordinatively
unsaturated Schiff base–titanium di(isopropoxide) com-
plex. The stereochemical outcome of the reaction was then
explained by the attack of an external nucleophile (either
trimethylsilyl or hydrogen cyanide) to the less hindered
face of the aldehyde carbonyl (Fig. 5). In particular, this
model successfully explained the crucial role played by
1
0b
8
aB (entry 10). In summary, salicylaldehyde Schiff base-
ligands 6 derived from the (S)-2-amino-2-ferrocenyl ethanols
1a–e are active catalysts in the asymmetric trimethylsilyl-
Pri
H
Pri
H
(
S)
H
H
O
O
O
O
N
N
Me
Pri
Pri
Ti
Me
Me
O
Ti
Me
O
O
O
O
H
O
Me
Me
Figure 5. Transition states for the enantioselective titanium-catalyzed trimethylsilyl cyanide addition to aldehydes, according to Oguni (Ref. 3b).
H
si
H
re
CN
CN
CN
R
Me
R

a
R. M Moreno et al. / Tetrahedron: Asymmetry 17 (2006) 1089–1103
1095
the C3
(
0
tert-butyl substituent in Schiff bases derived from
this prediction, since although 6cB affords (S)-9 in 93:7 er,
6dB produces (R)-9 with low enantioselectivity (compare
entries 5 and 6 in Table 2).
S)-configured 2-amino alcohols and salicylaldehyde 5B
in the blocking of the re face of the aldehyde.
In order to see if Oguni’s model could rationalize our
experimental results, we modelled the Schiff base–titanium
di(isopropoxide)–benzaldehyde complexes corresponding
to ligands 6aB, 6bB, 6cB, 6dB and 6eB, by means of the
We then next turned our attention to a second set of com-
plexes, in which one of the isopropoxy groups was replaced
with a cyanide one (Fig. 7). This type of complexes has re-
1
0c
cently been examined by Somanathan and Cole, building
3
2
34
SYBYL molecular mechanics model as implemented in
upon a previous proposal by Shibasaki.
3
3
the SPARTAN package of programs. For each complex,
four energetic minima were located, corresponding both to
different coordination sites of the aldehyde (syn or anti to
the ferrocenyl group) and to different orientations (IN or
As before, the Schiff base–titanium(isopropoxide)–cya-
nide–benzaldehyde complexes corresponding to ligands
6aB, 6bB, 6cB, 6dB and 6eB were modelled by means of
the SYBYL molecular mechanics force field. In this case,
1
3
OUT) of the latter. However, examination of the result-
ing models did not allow for the rationalization of experi-
mental results. Thus (see Fig. 6), the minimum energy
complexes corresponding to ligands 6cB (Fig. 6A) and
1
0c
eight energetic minima (corresponding to the fac-mer,
syn-anti and IN–OUT possible arrangements of the ligands
around the titanium) were located for each complex. We
were pleased to find that these models allowed for a ratio-
nalization of the observed trends in enantioselectivity. As
shown in Figure 8, the minimum energy complex for ligand
6cB (Fig. 8A) correctly predicts the predominant formation
6
dB (Fig. 6B) predict in every case the preferential attack
of the cyanide by the re face of benzaldehyde, leading to
S)-9. The experimental result, however, as we have dis-
(
cussed in the previous section, is at complete variance with
anti-IN
anti-OUT
Fe
Fe
iPr
iPr
Me
H
H
O
Me
O
H
O
N
O
O
Me
O
N
O
Ti
Ti
O
iPr
Me
iPr
Me
O
H
O
H
re
re
Me
Me
CN
CN
Me
Me
A
B
Figure 6. (A) Lowest energy transition state complex (SYBYL MM force field) for ligand 6cB, according to Oguni’s model. (B) Lowest energy transition
state complex for ligand 6dB.

a
1096
R. M Moreno et al. / Tetrahedron: Asymmetry 17 (2006) 1089–1103
Fe
Pri
Fe
N
C
R4
R4
O
H
O
Ti
H
R3
R3
O
N
O
N
O
Pri
Ti
R2
R2
O
C
R5
N
R5
O
O
H
H
R1
R1
mer-isomer
fac-isomer
Figure 7. Octahedral titanium transition state complex (mer and fac isomers) in the trimethylsilylcyanation of benzaldehyde, according to Somanathan
and Cole’s model (Ref. 10c).
mer-anti-IN
mer-anti-OUT
Fe
Fe
H
N
C
N
C
Me
H
H
Me
O
N
O
N
O
O
Ti
Ti
O
O
Me
O
O
Me
H
Me
iPr
H
re
iPr
Me
Me
CN
Me
Me
A
B
Figure 8. (A) Lowest energy transition state complex (SYBYL MM force field) for ligand 6cB, according to Somanathan and Cole’s model. (B) Lowest
energy transition state complex for ligand 6dB.
of cyanohydrin (S)-9; on the other hand, in the minimum
energy complex for 6dB (Fig. 8B), both the re and the si
faces of the benzaldehyde carbonyl are appreciably blocked
and one of the C methyls, respectively), in accordance
2
with the low enantioselectivity obtained with this ligand.
We therefore suggest that the cyanide-bound titanium
complexes proposed by Somanathan and Cole provide a
by substituents of the Schiff base-ligand (the C3 tert-butyl
0

a
R. M Moreno et al. / Tetrahedron: Asymmetry 17 (2006) 1089–1103
1097
13
1a,11a 1c,14 and 1d, 3-adamantyl-5-methyl-2-hydroxy-
benzaldehyde 5C and the ‘Schiff base 7 were prepared
according to the previously described procedures.
better description of the stereochemical course of the asym-
metric trimethylsilylcyanation of aldehydes than those for-
warded initially by Oguni.
8
b
3b
4.2. Synthesis of 1-amino-1-ferrocenyl-2-ethanol derivatives
3. Conclusions
4.2.1. 1-Ferrocenyl-1-propene 3. To a cold (0 ꢁC), stirred
In conclusion, the incorporation of 2-amino-2-ferro-
cenylalkanols 1a–e into salicylaldehyde Schiff bases gives
rise to a new class of chiral ligands, whose titanium alkox-
ide complexes are able to promote the asymmetric addition
of cyanotrimethylsilane to aldehydes. Both the enantio-
selectivity and stereochemical outcome of this process are
controlled by the positioning of substituents in the 2-ami-
no-2-ferrocenylethanol moiety. In particular, the titanium
complex of Schiff base 6cB, derived from (S)-2-amino-2-
ferrocenyl-2-propanol 1c and 3-tert-butyl-2-hydroxybenz-
aldehyde 5B, catalyzes the formation of the benzaldehyde
cyanohydrin (S)-9 in high yield (91%) and enantioselectiv-
ity (93:7 er). On the other hand, ligand 6dB, in which a
gem-dimethyl group has been introduced in the (S)-2-ami-
no-2-ferrocenylethanol moiety, affords the (R) enantiomer
of 9 with low enantioselectivity. The dependence of the cat-
alytic properties of these new ligands on the structure of the
substrate also appears to be different from that of the pre-
viously reported Schiff base–titanium complexes, as seen in
the asymmetric silylcyanation of the anisaldehyde regio-
isomers. On the other hand, molecular mechanics modelling
of the intermediate complexes (by means of the SYBYL
force field) is in good agreement with the experimental re-
sults of our study, and emphasize (a) the crucial role played
solution of ferrocenecarbaldehyde (3.0 g, 14 mmol) in
anhydrous tetrahydrofuran (40 ml), a 1.0 M solution of
ethylmagnesium bromide in tetrahydrofuran (21 ml,
21 mmol) was added dropwise. The resulting mixture was
stirred at room temperature for 30 min and cooled again
to 0 ꢁC. Saturated aqueous ammonium chloride (60 ml)
was added dropwise. After stirring for 5 min at room tem-
perature, the aqueous phase was separated and extracted
with ethyl acetate (3 · 60 ml). The combined organic
phases were washed with brine (50 ml), dried over sodium
sulfate and evaporated under reduced pressure. The crude
1-ferrocenyl-1-propanol (3.4 g, 14 mmol) was not purified
further. A solution of this alcohol in dry toluene (80 ml)
was heated at reflux in a Dean–Stark apparatus in the pres-
ence of neutral alumina (4.0 g, 0.04 mol) for 5 h. After
cooling to room temperature, the solvent was eliminated
under vacuum and the residue purified by column chroma-
tography (silica gel, hexanes as eluent) to afford 2.70 g
1
(85% yield) of olefins 3 (ca. 4:1 (E)/(Z) mixture). The H
NMR data for these compounds were identical to those
1
6
reported in the literature.
4.2.2. (1S,2R)-1-Ferrocenylpropane-1,2-diol 2. To a stir-
red solution of K Fe(CN) (6.2 g, 19 mmol) and K CO
3
6
2
3
by the C2
0
tert-butyl substituent in the Schiff base, and (b)
(2.6 g, 19 mmol) in 1:1 acetonitrile–water (350 ml), were
added (DHQD) PYR (0.29 g, 0.30 mmol) and K OsO -
the displacement of one of the isopropoxides on the tita-
nium centre by a non-reactive cyanide ion, leading to the
formation of a more compact transition state complex.
2
2
2
(OH) (49 mg, 0.30 mmol), and stirring was maintained at
4
room temperature until complete dissolution of the osmate
(2 h). At this point, 1-ferrocenylpropene 3 (1.4 g, 6.3 mmol,
4:1 (E)/(Z) mixture), dissolved in the minimum amount of
4
. Experimental
acetonitrile, was added in one portion. The reaction was
monitored by TLC. When no starting alkenylferrocene
remained (75 min stirring at room temperature), sodium
sulfite (9.9 g, 76 mmol) was added and stirring maintained
for 30 min. The reaction mixture was extracted with ethyl
acetate (5 · 60 ml), the organic extracts were dried over
magnesium sulfate and the solvents removed at reduced
pressure. Column chromatography of the crude product
(silica gel, hexane–ethyl acetate mixtures as eluent) affor-
ded 1.3 g (81% yield) of (1S,2R)-1-ferrocenylpropane-1,2-
diol (98:2 er, determined by HPLC on a Chiral PAK AD
4
.1. General materials and methods
Melting points were determined in an open capillary tube
and are uncorrected. Optical rotations were measured at
room temperature (23 ꢁC); concentrations are given in
g 100 ml . Infrared spectra were recorded in a Fourier
transform mode, using NaCl film or KBr pellet techniques.
Unless otherwise stated, NMR spectra were recorded in
ꢀ1
CDCl solution. Chemical shifts are given in parts per mil-
lion and referenced to TMS or CHCl . Carbon multiplici-
3
1
5
15
column ) as a yellow solid. Mp: 72.4–73.8 ꢁC (lit: 69–
3
23
D
15
ties were established by DEPT experiments. Mass spectra
were performed using chemical ionization (CI) or electro-
spray ionization (ESI) techniques. Exact mass measure-
ments (HRMS) were performed by the ‘Unidad de
Espectrometr ´ı a de Masas de la Universidad de Santiago
de Compostela’. Reactions (with the exception of catalytic
asymmetric dihydroxylations) were generally run in flame-
71 ꢁC). ½aꢁ ¼ þ80:5 (c 0.21, CH Cl ) [lit: +73.1 (c
2 2
2
2
1
0.14, CH Cl )]. H NMR (200 MHz): d 1.07 (d, J =
6.2 Hz, 3H), 2.27 (br s, 1H), 2.54 (br s, 1H), 3.66 (m,
1H), 4.05 (m, 1H), 4.20–4.26 (m, 9H) ppm.
4.2.3. (1S,2R)-1-Azido-1-ferrocenyl-2-propyl acetate 4. To
a stirred solution of (1S,2R)-1-ferrocenyl-2-propane-1,2-
diol 2 (3.80 g, 14.5 mmol) in anhydrous pyridine (20 ml),
acetic anhydride (30 ml, 0.36 mol) was added and the
resulting mixture stirred at room temperature for 12 h.
At this point, TLC monitoring revealed that no starting
diol remained; excess acetic anhydride and pyridine
were removed under vacuum, the addition of toluene
or oven-dried glassware under a N atmosphere. Commer-
2
cially available reagents were used as received. Diethyl
ether and tetrahydrofuran used in the reactions were dried
by distillation over metallic sodium and benzophenone (or
fluorenone). Dichloromethane, triethylamine and pyridine
were distilled from calcium hydride. Amino alcohols

a
1098
R. M Moreno et al. / Tetrahedron: Asymmetry 17 (2006) 1089–1103
(
3 · 15 ml) being necessary to ensure the complete removal
ethanol (2.2 ml) was added via a cannula. The mixture
was stirred at room temperature under a hydrogen atmo-
sphere (balloon) for 12 h, filtered through a Celite pad
of pyridine. In this way, 4.8 g (quantitative yield) of the
crude diacetate of 2 was obtained as an orange oil. Without
further purification, this product was used directly in the
following step. H NMR (200 MHz): d 1.09 (d, J =
6
(
(
(
(
(
ꢂ
and the solvent removed under vacuum, to afford 170 mg
(quantitative yield) of the title compound as a yellow solid.
1
23
.6 Hz, 3H), 2.01 (s, 3H), 2.19 (s, 3H), 4.16 (m, 9H), 5.02
Mp: 141.2–142.8 ꢁC. ½aꢁ ¼ ꢀ11:5 (c 0.26, CH Cl ). IR
D
2
2
1
3
ꢀ1
1
m, 1H), 5.80 (d, J = 5.8 Hz, 1H) ppm.
C NMR
(KBr): m
= 3373, 3091, 2925, 1455, 1030, 814 cm . H
max
50 MHz): d 16.4 (CH ), 21.0 (CH ), 21.1 (CH ), 66.4
NMR (200 MHz): d 2.11 (br s, 3H, NH +OH), 3.84 (m,
3
3
3
2
CH), 67.5 (CH), 67.8 (CH), 68.1 (CH), 68.7 (CH), 68.8
CH), 72.0 (CH), 84.6 (Cq, Fc), 170.0 (Cq, CO), 170.3
Cq, CO) ppm.
2H), 4.06–4.23 (m, 8H), 4.48 (d, J = 4.8 Hz, 1H, CH–
1
3
OH), 7.2–7.4 (m, 5H, Ph) ppm. C NMR (75 MHz): d
57.1 (CH–N), 65.3 (CH, Fc), 67.6 (CH, Fc), 68.1 (CH,
Fc), 68.3 (CH, Fc), 68.6 (CH, Fc), 77.5 (CH–O), 90.8
(Cq, Fc), 126.5 (CH, Ph), 127.4 (CH, Ph), 128.3 (CH,
To a stirred solution of the crude diacetate of 2 (4.8 g,
3.9 mmol) in 3:1 water–methanol (275 ml), sodium azide
10.0 g, 0.15 mol) was added in one portion. The resulting
1
(
Ph), 142.2 (Cq, Ph) ppm. MS (CI, NH ) m/e: 322 (M+1,
3
100%), 305 (Mꢀ16, 71%). HRMS (CI) C H FeNO (M):
1
8
19
mixture was stirred at 60 ꢁC for 4.5 h (TLC monitoring)
and allowed to cool at room temperature. After eliminating
most of the methanol at reduced pressure, the mixture was
extracted with dichloromethane (4 · 60 ml). The combined
organic extracts were washed with brine (2 · 80 ml), dried
over magnesium sulfate, stripped of solvents at reduced
pressure and purified by column chromatography (silica
gel, hexane–ethyl acetate mixtures of increasing polarity)
to afford 3.20 g (70% yield) of azido acetate 4 as an or-
calcd 321.0816, found 321.0810.
4.3. Synthesis of salicylaldehyde Schiff bases
4.3.1. Typical procedure. Preparation of 2-[((S)-1-ferrocen-
yl-2-hydroxyethylimino)methyl]phenol 6aA. To a solu-
tion of amino alcohol 1a (300 mg, 1.23 mmol) in absolute
ethanol (6.2 ml) was added 0.129 ml (1.23 mmol) of salicyl-
aldehyde 5A. After stirring for 1 h at room temperature
(TLC monitoring), the solvent was distilled off under vac-
uum and the residue was purified by column chromato-
graphy on silica gel (eluting with hexane–ethyl acetate
23
ange-coloured oil. ½aꢁ ¼ þ91:3 (c 0.56, CHCl ). IR (NaCl
D
3
film): m
8
= 3080, 2910, 2100, 1740, 1380, 1250, 1050,
H NMR (200 MHz): d 1.16 (d, J = 6.2 Hz,
max
.
ꢀ
1
1
00 cm
3
H), 2.08 (s, 3H), 4.11–4.20 (m, 10H), 5.04 (m, 1H) ppm.
mixtures) to give 328 mg (77% yield) of the Schiff base
1
3
23
C NMR (50 MHz): d 17.1 (CH ), 21.2 (CH ), 65.2
6aA as a yellow solid. Mp: 109.7–111.1 ꢁC. ½aꢁ ¼ þ203:0
3
3
D
(CH), 66.7 (CH), 67.9 (CH), 68.0 (CH), 68.2 (CH), 68.9
(CH), 73.2 (CH), 85.2 (Cq, Fc), 170.0 (Cq, CO) ppm. MS
(ESI) m/e: 327 (M, 100%), 285 (Mꢀ42, 94%). HRMS
(ESI) C H FeN O (M): calcd 327.0670, found 327.0663.
(c 0.28, EtOH). IR (KBr): m
1279, 1040, 820, 756 cm . H NMR (300 MHz): d 1.5–
= 3095, 2925, 1630, 1459,
max
ꢀ
1 1
1.8 (br s, 1H, OH), 3.88 (m, 2H, CH OH), 4.10–4.23 (m,
2
10H, Fc+CH–N), 6.92 (t, J = 7.5 Hz, 1H, Ar), 7.01 (d,
J = 8.1 Hz, 1H, Ar), 7.35 (m, 2H, Ar), 8.51 (s, 1H,
1
5
17
3
2
1
3
4
.2.4. (1S,2R)-1-Amino-1-ferrocenyl-2-propanol 1b. To a
CH@N), 13.2–13.8 (br s, 1H, OH Ar) ppm. C NMR
cold (0 ꢁC), stirred suspension of lithium aluminium
hydride (366 mg, 9.64 mmol) in anhydrous tetrahydrofuran
(100 MHz): d 66.3 (CH), 66.8 (CH), 67.1 (CH ), 67.7
2
(CH), 68.1 (CH), 68.6 (CH), 70.4 (CH), 87.0 (Cq, Fc),
117.1 (CH, Ar), 118.4 (Cq, Ar), 118.7 (CH, Ar), 131.6
(CH, Ar), 132.6 (CH, Ar), 161.2 (Cq, Ar, C–OH), 165.3
(
36 ml), a solution of azido acetate 4 (1.05 g, 3.21 mmol)
in anhydrous tetrahydrofuran (24 ml) was added via a can-
nula. The mixture was stirred at room temperature for
(CH, CH@N) ppm. MS (CI, NH ) m/e: 348 (M+1,
3
4
0 min, cooled again to 0 ꢁC and treated successively with
100%). HRMS (CI) C H FeNO (M): calcd 347.0820,
1
9
19
2
water (1.3 ml), aqueous 15% NaOH (1.6 ml) and again
water (1.9 ml). After stirring for 5 min at rt, the mixture fil-
found 347.0821.
ꢂ
tered through a Celite pad, the precipitate was washed
with ethyl acetate and the solvents were removed under
vacuum, to afford 874 mg (100% yield) of the title com-
4.3.2. 2-[((1S,2R)-1-Ferrocenyl-2-hydroxypropylimino)meth-
yl]phenol 6bA. In a similar way, salicylaldehyde 5A
(0.120 ml, 1.13 mmol) and amino alcohol 1b (300 mg,
1.16 mmol) in absolute ethanol (10.2 ml, 100 min at room
temperature) afforded 379 mg (92% yield) of the title com-
23
pound as a yellow solid. Mp: 62.3–65.1 ꢁC. ½aꢁ ¼ þ70:1
D
(
c 0.56, CHCl ). IR (NaCl film): m
= 3380, 3300, 3080,
max
3
ꢀ1
1
2
900, 1570, 1450, 1380, 1080, 1000, 1105, 800 cm . H
NMR (200 MHz): d 1.10 (d, J = 6.2 Hz, 3H), 2.30 (br s,
H, NH +OH), 3.36 (d, J = 6.0 Hz, 1H, CH–N), 3.49
pound as
a
yellow solid. Mp: 116.5–118.0 ꢁC.
23
½aꢁ ¼ þ481:0 (c 0.57, EtOH). IR (KBr): m
= 3365,
max
D
ꢀ
1
1
3
2971, 1632, 1461, 1279, 1045, 818, 756 cm . H NMR
2
1
3
(
(
(
m, 1H, CH–O), 4.16 (m, 9H, Fc) ppm. C NMR
50 MHz): d 19.9 (CH ), 56.9 (CH), 64.7 (CH), 67.6
CH), 67.7 (CH), 68.3 (CH), 71.7 (CH), 91.8 (Cq, Fc)
(300 MHz): d 1.10 (d, J = 6.0 Hz, 3H, CH ), 1.6–1.9 (br
3
s, 1H, OH), 3.82 (m, 1H, CH–CH ), 3.88 (d, J = 6.6 Hz,
3
3
1H, CH–N), 4.04 (m, 5H, Fc), 4.16 (m, 1H, Fc), 4.20 (m,
ppm. MS (ESI) m/e: 260 (M+1, 23%), 243 (Mꢀ16,
2H, Fc), 4.27 (m, 1H, Fc), 6.90 (td, J = 7.3 Hz,
1
1
00%). HRMS (ESI) C H FeNO (M+1): calcd
J2 = 1.0 Hz, 1H, Ar), 7.03 (d, J = 8.1 Hz, 1H, Ar), 7.34–
7.40 (m, 2H, Ar), 8.54 (s, 1H, CH@N), 13.4–13.6 (br s,
1
3
18
2
60.0738, found 260.0733.
1
3
1
H, OH Ar) ppm. C NMR (50 MHz): d 19.4 (CH3),
4
.2.5. (1R,2S)-2-Amino-2-ferrocenyl-1-phenylethanol 1e.
66.4 (CH), 66.8 (CH), 67.4 (CH), 67.9 (CH), 68.2 (CH),
68.6 (CH), 71.6 (CH), 75.8 (CH), 87.9 (Cq, Fc), 117.1
(CH, Ar), 118.1 (Cq, Ar), 118.8 (CH, Ar), 132.6 (CH,
Ar), 160.5 (Cq, Ar, C–OH), 165.0 (CH, CH@N) ppm.
To a stirred suspension of PtO (18 mg) in absolute ethanol
2
(
3 ml), a solution of (1R,2S)-2-azido-2-ferrocenyl-1-phenyl-
1
1b
ethanol
(182 mg, 0.52 mmol; 99.5:0.5 er) in absolute

a
R. M Moreno et al. / Tetrahedron: Asymmetry 17 (2006) 1089–1103
1099
t
t
MS (CI, NH ) m/e: 364 (M+1, 100%). HRMS (CI)
(CH ), 29.4 (CH , Bu), 34.9 (Cq, Bu), 66.4 (CH), 67.2
3
3
3
C H FeNO (M): calcd 363.0917, found 363.0922.
(CH), 68.1 (CH), 68.2 (CH), 68.6 (CH), 71.6 (CH), 75.8
CH), 88.3 (Cq, Fc), 118.0 (CH, Ar), 118.2 (Cq, Ar),
2
0
21
2
(
4
.3.3. 2-[((S)-1-Ferrocenyl-2-hydroxy-2-methylpropylimino)-
methyl]phenol 6dA. In a similar way, salicylaldehyde 5A
38 ll, 0.36 mmol) and amino alcohol 1d (100 mg,
.37 mmol) in absolute ethanol (1.8 ml, 70 min at room
temperature) afforded 122 mg (90% yield) of the title com-
129.7 (CH, Ar), 129.9 (CH, Ar), 137.5 (Cq, Ar), 160.5
(Cq, Ar, C–OH), 165.8 (CH, CH@N) ppm. MS (CI,
(
0
NH ) m/e: 419 (M, 100%), 420 (M+1, 30%). HRMS (CI)
3
C H FeNO (M): calcd 419.1548, found 419.1538.
2
4
29
2
23
pound as a yellow solid. Mp: 167.4–168.9 ꢁC. ½aꢁ
¼
4.3.6. 2-tert-Butyl-6-[((S)-1-ferrocenyl-2-hydroxy-1-methyl-
ethylimino)methyl]phenol 6cB. In a similar way, 3-tert-
butyl-2-hydroxybenzaldehyde 5B (26 ll, 0.21 mmol) and
amino alcohol 1c (55 mg, 0.22 mmol) in absolute ethanol
(1.5 ml, 4 h at room temperature) afforded 65 mg (75%
yield) of the title compound as a yellow solid. Mp: 67.0–
D
þ443:0 (c 0.29, EtOH). IR (KBr): m
= 3365, 3475,
max
ꢀ
1
1
2
926, 1630, 1501, 1385, 1281, 1026, 810, 756 cm . H
NMR (300 MHz): d 1.14 (s, 3H, CH ), 1.15 (s, 3H, CH ),
3
3
1
4
6
7
1
2
.5 (br s, 1H, OH), 3.94 (s, 1H, CH–N), 4.0 (s, 5H, Fc),
.18 (m, 2H, Fc), 4.26 (m, 1H, Fc), 4.31 (m, 1H, Fc),
.94 (t, J = 7.6 Hz, 1H, Ar), 7.04 (d, J = 7.8 Hz, 1H, Ar),
.34–7.42 (m, 2H, Ar), 8.58 (s, 1H, CH@N), 13.6 (br s,
23
67.8 ꢁC. ½aꢁ ¼ þ139:2 (c 1.20, EtOH). IR (NaCl film):
D
m
= 3404, 3096, 2956, 1626, 1439, 1267, 1108, 1035,
max
1
3
ꢀ1
1
H, OH Ar) ppm. C NMR (50 MHz): d = 25.6 (CH3),
856 cm . H NMR (400 MHz): d 1.48 (s, 9H, 3 · CH ),
1.66 (s, 3H, CH ), 2.00 (br s, 1H, OH), 3.75–3.86 (m, 2H,
3
6.2 (CH ), 67.3 (CH), 68.2 (CH), 68.6 (CH), 73.1 (Cq,
3
3
C–OH), 79.4 (CH, CH–N), 87.8 (Cq, Fc), 117.1 (CH,
CH OH), 4.19–4.26 (m, 9H, Fc), 6.82 (t, J = 7.8 Hz, 1H,
2
Ar), 118.4 (Cq, Ar), 118.8 (CH, Ar), 131.6 (CH, Ar),
Ar), 7.13 (dd, J = 7.6 Hz, J = 1.6 Hz, 1H, Ar), 7.35 (d,
1
2
1
32.6 (CH, Ar), 161.1 (Cq, Ar, C–OH), 164.9 (CH,
J = 8.0 Hz, 1H, Ar), 8.32 (s, 1H, CH@N) ppm. The signal
CH@N) ppm. MS (CI, NH ) m/e: 377 (M, 100%), 378
corresponding to the phenol hydroxyl proton was not ob-
3
1
3
(
M+1, 27%). HRMS (CI) C H FeNO (M): calcd
served. C NMR (100 MHz): d 22.5 (CH ), 29.3 (CH ),
3 3
t
2
1
23
2
3
77.1078, found 377.1092.
34.8 (Cq, Bu), 63.2 (Cq, CH-Fc), 66.4 (CH, Fc), 67.9
CH, Fc), 68.2 (CH, Fc), 68.8 (CH, Fc), 71.0 (CH ), 92.5
(
2
4
.3.4. 2-tert-Butyl-6-[((S)-1-ferrocenyl-2-hydroxyethylimino)-
(Cq, Fc), 117.6 (CH, Ar), 118.5 (Cq, Ar), 129.4 (CH,
methyl]phenol 6aB. In a similar way, 3-tert-butyl-2-
hydroxybenzaldehyde 5B (137 ll, 0.80 mmol) and amino
alcohol 1a (200 mg, 0.82 mmol) in absolute ethanol
Ar), 130.1 (CH, Ar), 137.5 (Cq, Ar), 160.8 (Cq, Ar, C–
OH), 163.3 (CH, CH@N) ppm. MS (CI, NH ) m/e: 420
3
(M+1, 100%), 243 (Mꢀ178, 40%). HRMS (CI) C H Fe-
2
4
29
(
4.1 ml, 4.5 h at room temperature) afforded 295 mg (89%
NO (M): calcd 419.1548, found 419.1540.
2
yield) of the title compound as a yellow solid. Mp: 67.0–
2
D
3
6
7.8 ꢁC. ½aꢁ ¼ þ469:0 (c 0.21, EtOH). IR (NaCl film):
4.3.7. 2-tert-Butyl-6-[((S)-1-ferrocenyl-2-hydroxy-2-methyl-
propylimino)methyl]phenol 6dB. In a similar way, 3-tert-
butyl-2-hydroxybenzaldehyde 5B (92 ll, 0.54 mmol) and
amino alcohol 1d (150 mg, 0.55 mmol) in absolute ethanol
(2.8 ml, 6 h at room temperature) afforded 217 mg (93%
yield) of the title compound as a yellow solid. Mp: 91.0–
m
= 3384, 2956, 1628, 1559, 1437, 1267, 1040, 818,
max
ꢀ
1 1
7
1
52 cm . H NMR (300 MHz): d 1.47 (s, 9H, 3 · CH ),
3
.7 (br s, 1H, OH), 3.89 (m, 2H, CH OH), 4.13 (s, 5H,
2
Fc), 4.16–4.20 (m, 4H, Fc), 6.86 (t, J = 7.8 Hz, 1H, Ar),
.19 (dd, J = 7.4 Hz, J = 1.6 Hz, 1H, Ar), 7.36 (dd,
7
1
2
23
J = 7.8 Hz, J = 1.6 Hz, 1H, Ar), 8.51 (s, 1H, CH@N),
3.9 (br s, 1H, OH Ar) ppm. C NMR (50 MHz): d 29.4
CH ), 34.9 (Cq, Bu), 66.4 (CH), 66.9 (CH), 67.1 (CH ),
93.5 ꢁC. ½aꢁ ¼ þ419:2 (c 0.23, EtOH). IR (NaCl film):
1
2
D
1
3
1
(
m
= 3426, 2962, 1630, 1437, 1385, 1268, 1146, 1067,
max
t
ꢀ1
1
751 cm . H NMR (300 MHz): d 1.15 (s, 3H, CH3–
3
2
6
7.7 (CH), 68.1 (CH), 68.7 (CH), 70.3 (CH), 87.2 (Cq,
COH), 1.17 (s, 3H, CH –COH), 1.50 (s, 9H, 3 · CH ),
3
3
Fc), 117.9 (CH, Ar), 118.3 (Cq, Ar), 129.7 (CH, Ar),
1
1
1
1.56 (br s, 1H, OH), 3.91 (s, 1H, CH-Fc), 3.99 (s, 5H,
Fc), 4.16–4.20 (m, 2H, Fc), 4.38 (m, 1H, Fc), 6.88 (t,
J = 7.2 Hz, Ar), 7.24 (dd, J = 7.4 Hz, J = 1.8 Hz, 1H,
29.9 (CH, Ar), 137.5 (Cq, Ar), 160.4 (Cq, Ar, C–OH),
66.0 (CH, CH@N) ppm. MS (CI, NH ) m/e: 405 (M,
3
1
2
00%), 406 (M+1, 27%). HRMS (CI) C H FeNO (M):
Ar), 7.39 (dd, J = 7.4 Hz, J = 1.4 Hz, 1H, Ar), 8.57 (s,
2
3
27
2
1 2
1
3
calcd 405.1391, found 405.1375.
1H, CH@N), 14.7 (br s, 1H, OH Ar) ppm. C NMR
50 MHz): d 25.6 (CH ), 26.3 (CH ), 29.3 (CH , Bu),
3 3 3
t
t
(
4
.3.5.
2-tert-Butyl-6-[((1S,2R)-1-ferrocenyl-2-hydroxy-
34.9 (Cq, Bu), 67.1 (CH), 67.3 (CH), 68.1 (CH), 68.5
(CH), 73.1 (Cq, C–OH), 79.3 (CH), 88.0 (Cq, Fc), 117.9
(CH, Ar), 118.2 (Cq, Ar), 129.7 (CH, Ar), 129.9 (CH,
Ar), 137.4 (Cq, ar), 160.4 (Cq, Ar, C–OH), 165.7 (CH,
propylimino)methyl]phenol 6bB. In a similar way, 3-tert-
butyl-2-hydroxybenzaldehyde 5B (65 ll, 0.37 mmol) and
amino alcohol 1b (100 mg, 0.38 mmol) in absolute ethanol
(
4.5 ml, 5 h at room temperature) afforded 160 mg (99%
CH@N) ppm. MS (CI, NH ) m/e: 434 (M+1, 100%).
3
yield) of the title compound as a yellow solid. Mp: 52.5–
5
m
7
3
3
2
7
HRMS (CI) C H FeNO (M+1): calcd 434.1782, found
2
5
32
2
23
4.6 ꢁC. ½aꢁ ¼ þ469:0 (c 0.21, EtOH). IR (NaCl film):
434.1761.
D
= 3373, 2960, 1632, 1437, 1306, 1268, 1044, 818,
max
ꢀ
1
1
52 cm
.
H NMR (300 MHz): d 1.11 (d, J = 6.0 Hz,
4.3.8. 2-Adamantyl-5-methyl-6-[((S)-1-ferrocenyl-2-hydroxy-
ethylimino)methyl]phenol 6aC. In a similar way, 3-ada-
mantyl-5-methyl-2-hydroxybenzaldehyde 5C (158 mg,
0.58 mmol) and amino alcohol 1a (150 mg, 0.61 mmol) in
absolute ethanol (4 ml, 15 min at 50 ꢁC) afforded 181 mg
H, CH –OH), 1.49 (s, 9H, 3 · CH ), 1.9 (br s, 1H, OH),
3
3
.84 (m, 2H), 4.04 (s, 5H, Fc), 4.15 (m, 1H, Fc), 4.21 (m,
H, Fc), 4.33 (m, 1H, Fc), 6.87 (t, J = 7.6 Hz, 1H, Ar),
.23 (dd, J = 7.8 Hz, J = 1.4 Hz, 1H, Ar), 7.38 (dd,
1
2
J = 7.8 Hz, J = 1.4 Hz, 1H, Ar), 8.54 (s, 1H, CH@N),
1
(63% yield) of the title compound as a yellow solid. Mp:
1
2
1
3
23
4.0 (br s, 1H, OH Ar) ppm. C NMR (50 MHz): d 19.4
108.4–109.6 ꢁC. ½aꢁD ¼ þ204:2 (c 0.36, EtOH). IR (KBr):

a
1100
R. M Moreno et al. / Tetrahedron: Asymmetry 17 (2006) 1089–1103
mmax = 3398, 3095, 2904, 2850, 1628, 1596, 1455, 1248,
mantyl), 38.0 (CH adamantyl), 41.2 (CH adamantyl),
2 2
64.0 (Cq, C-Fc), 67.1 (CH), 67.5 (CH), 68.3 (CH), 68.7
ꢀ
1
1
1
040, 816 cm
.
H NMR (400 MHz): d 1.60–1.84 (m,
7
H, –OH+3 · (CH ) adamantyl), 2.09 (m, 3H, 3 · (CH)
(CH), 69.6 (CH), 71.1 (CH ), 95.6 (Cq, Fc), 119.7 (Cq,
Ar), 127.0 (Cq, Ar), 130.9 (CH, Ar), 131.0 (CH, Ar),
2
2
adamantyl), 2.21 (m, 6H, 3 · (CH ) adamantyl), 2.30 (s,
3
4
2
H, CH ), 3.81–3.91 (m, 2H, CH OH), 4.13 (s, 5H, Fc),
160.1 (Cq, Ar, C–OH), 164.2 (CH, CH@N) ppm. MS
3
2
.16–4.19 (m, 4H, Fc), 4.25–4.26 (m, 1H, CH-Fc), 6.97
(CI, NH ) m/e: 511 (M, 10%), 512 (M+1, 100%). HRMS
3
(
(
(
(
(
(
s, 1H, Ar), 7.11 (s, 1H, Ar), 8.45 (s, 1H, CH@N), 13.7
(CI) C H FeNO (M): calcd 511.2174, found 511.2192.
3
1
37
2
1
3
br s, 1H, OH Ar) ppm. C NMR (100 MHz): d 20.7
CH ), 29.1 (CH adamantyl), 37.0 (Cq, adamantyl), 37.1
4.4. Reduction of salicylaldehyde Schiff bases derived from
2-ferrocenyl-2-amino alcohols
3
CH adamantyl), 40.3 (CH adamantyl), 66.5 (CH), 66.9
2
2
CH), 67.1 (CH ), 67.8 (CH), 68.0 (CH), 68.7 (CH), 70.5
2
CH), 87.3 (Cq, Fc), 118.1 (Cq, Ar), 126.9 (Cq, Ar),
29.7 (CH, Ar), 130.9 (CH, Ar), 137.5 (Cq, Ar), 158.5
4.4.1. Representative experimental procedure. Preparation
2-[((S)-1-ferrocenyl-2-hydroxy-2-methylpropylamino)-
1
of
(
Cq, Ar, C–OH), 166.3 (CH, CH@N) ppm. MS (CI,
methyl]phenol 8dA. To a cold (ꢀ78 ꢁC), stirred solution
of 2-[((S)-1-ferrocenyl-2-hydroxy-2-methylpropylimino)-
methyl]phenol 6dA (50 mg, 0.13 mmol) and cerium(III)
chloride heptahydrate (49 mg, 0.13 mmol) in methanol
(2.1 ml), sodium borohydride (10 mg, 0.26 mmol) was
added in one portion. The resulting mixture was stirred
at room temperature for 75 min (TLC monitoring), and a
saturated aqueous solution of ammonium chloride (5 ml)
was added dropwise. The reaction mixture was extracted
with dichloromethane (3 · 6 ml) and washed with brine
(10 ml). After drying over magnesium sulfate, elimination
of the solvents followed by chromatographic purification
on silica gel using hexane–ethyl acetate mixtures as eluents
gave 38 mg (77% yield) of the title compound as a yellow
NH ) m/e: 497 (M, 100%), 498 (M+1, 32%). HRMS (CI)
C H FeNO (M): calcd 497.2018, found 497.2016.
3
3
0
35
2
4
.3.9. 2-Adamantyl-5-methyl-6-[((S)-1-ferrocenyl-2-hydroxy-
propylimino)methyl]phenol 6bC. In a similar way, 3-ada-
mantyl-5-methyl-2-hydroxybenzaldehyde 5C (160 mg,
0
.59 mmol) and amino alcohol 1b (157 mg, 0.60 mmol) in
absolute ethanol (5 ml, 1.5 h at 50 ꢁC) afforded 270 mg
(
88% yield) of the title compound as a yellow solid. Mp:
23
8
m
1
6
9.5–91.1 ꢁC. ½aꢁ ¼ þ408:3 (c 0.57, EtOH). IR (KBr):
D
= 3407, 2900, 2845, 1635, 1541, 1456, 1249,
max
ꢀ
1
1
050 cm
.
H NMR (400 MHz): d 1.02 (d, 3H, J =
.4 Hz, CH ), 1.84 (m, 6H, 3 · (CH ) adamantyl), 2.10
3
2
23
(
m, 3H, 3 · (CH) adamantyl), 2.26 (m, 6H, 3 · (CH ) ada-
solid. Mp: 93.9–94.6 ꢁC. ½aꢁ ¼ þ61:9 (c 1.35, EtOH). IR
2
D
mantyl), 2.29 (s, 3H, CH Ar), 3.76 (m, 1H, CH–CH ), 3.89
(KBr): m
= 3300, 3091, 2973, 2853, 1616, 1589, 1489,
max
3
3
ꢀ1
1
(
d, J = 7.2 Hz, 1H, CH-Fc), 3.97 (br s, 1H, OH), 4.03 (s,
H, Fc), 4.14 (s, 1H, Fc), 4.21 (s, 1H, Fc), 4.28 (s, 1H,
Fc), 4.31 (s, 1H, Fc), 7.12 (s, 1H, Ar), 7.13 (s, 1H, Ar),
1254, 1001, 754 cm . H NMR (400 MHz): d 1.15 (s,
5
6H, 2 · CH ), 3.22 (s, 1H, CH–N), 4.12 (s, 1H, Fc), 4.17–
3
4.20 (m, 8H, Fc), 4.30 (m, 2H, CH –N), 6.81 (t,
2
8
.60 (s, 1H, CH@N) ppm. The signal corresponding to
J = 7.6 Hz, 1H, Ar), 6.91 (d, J = 8.0 Hz, 1H, Ar), 7.08
(d, J = 7.2 Hz, 1H, Ar), 7.20 (t, J = 7.2 Hz, 1H, Ar) ppm.
The signals corresponding to the OH and to the NH pro-
1
3
the phenol proton was not observed.
C NMR
(
100 MHz): d 20.3 (CH ), 20.6 (CH , Ar), 29.9 (CH ada-
3 3
1
3
mantyl), 37.5 (Cq adamantyl), 37.7 (CH2 adamantyl),
tons were not observed. C NMR (50 MHz): d 25.4
4
6
9
0.9 (CH adamantyl), 66.9 (CH), 67.5 (CH), 68.5 (CH),
9.2 (CH), 69.3 (CH), 71.7 (CH, CH–OH), 76.7 (CH),
0.1 (Cq, Fc), 119.4 (Cq, Ar), 127.2 (Cq, Ar), 130.6 (CH,
(CH ), 26.7 (CH ), 54.7 (CH ), 65.6 (CH), 66.9 (CH),
2
3
3
2
67.5 (CH), 68.0 (CH), 68.6 (CH), 69.6 (CH), 74.1 (Cq,
C–OH), 89.3 (Cq, Fc), 116.4 (CH, Ar), 119.3 (CH, Ar),
123.7 (Cq, Ar), 128.1 (CH, Ar), 128.9 (CH, Ar), 157.7
Ar), 130.8 (CH, Ar), 137.6 (Cq, Ar), 159.3 (Cq, Ar, C–
OH), 166.4 (CH, CH@N) ppm. MS (CI, NH ) m/e: 512
(Cq, Ar, C–OH) ppm. MS (CI, NH ) m/e: 380 (M+1,
3
3
(
M+1, 100%). HRMS (CI) C H FeNO (M+1): calcd
100%), 320 (Mꢀ59, 36%). HRMS (CI) C H FeNO
21 26
3
1
38
2
2
5
12.2252, found 512.2235.
(M+1): calcd 380.1313, found 380.1301.
4
.3.10. 2-Adamantyl-5-methyl-6-[((S)-1-ferrocenyl-2-hydr-
4.4.2. 2-tert-Butyl-6-[((S)-1-ferrocenyl-2-hydroxyethylamino)-
methyl]phenol 8aB. In a similar way, 125 mg (0.31 mmol)
of 6aB was treated with sodium borohydride (24 mg,
0.62 mmol) and cerium(III) chloride heptahydrate (116
mg, 0.31 mmol) in methanol (5 ml, 75 min at room temper-
oxy-1-methylethylimino)methyl]phenol 6cC. In a similar
way, 3-adamantyl-5-methyl-2-hydroxybenzaldehyde 5C
(
92 mg, 0.34 mmol) and amino alcohol 1c (90 mg,
.35 mmol) in absolute ethanol (2.5 ml, 1 h at 50 ꢁC) affor-
ded 151 mg (87% yield) of the title compound as a yellow
0
ature) to afford 60 mg (48% yield) of the title compound as
23
23
solid. Mp: 94.7–95.9 ꢁC. ½aꢁ ¼ þ137:6 (c 0.50, EtOH).
a yellow semi-solid. ½aꢁ ¼ þ13:4 (c 0.40, EtOH). IR (NaCl
D
D
IR (KBr): m
= 3359, 2903, 2849, 1626, 1453, 1250,
H NMR (400 MHz): d 1.72 (s, 3H,
film): m
= 3305, 2921, 2853, 1736, 1651, 1592, 1437,
max
max
ꢀ
1
1
ꢀ1
1
1
046, 818 cm
.
1239, 1024, 749 cm . H NMR (400 MHz): d 1.44 (s,
CH -Fc), 1.88 (m, 6H, 3 · (CH ) adamantyl), 2.14 (m,
9H, 3 · CH ), 3.56 (m, 1H, CH-Fc), 3.82 (m, 1H, CH –
3
2
3
2
3
H, 3 · (CH) adamantyl), 2.30 (m, 6H, 3 · (CH ) adamant-
OH), 3.96 (d, J = 13.6 Hz, 1H, CH –N), 4.04 (d,
2
2
yl), 2.33 (s, 3H, CH ), 2.8–2.9 (br s, 1H, OH), 3.75 (d,
J = 13.6 Hz, 1H, CH –N), 4.05 (m, 1H, CH –OH), 4.17–
3
2
2
J = 10.4 Hz, 1H, CH OH), 3.88 (d, J = 10.4 Hz, 1H,
4.21 (m, 9H, Fc), 6.74 (t, J = 7.6 Hz, Ar), 6.88 (dd,
J = 7.6 Hz, J = 1.6 Hz, 1H, Ar), 7.21 (dd, J = 7.6 Hz,
2
CH OH), 4.24 (m, 6H, Fc), 4.28 (s, 1H, Fc), 4.30–4.32
2
1
2
1
(
1
m, 2H, Fc), 7.10 (s, 1H, Ar), 7.14 (s, 1H, Ar), 8.55 (s,
H, CH@N) ppm. The signal corresponding to the phenol
J = 1.6 Hz, 1H, Ar) ppm. The signals corresponding to
2
1
3
the OH and to the NH protons were not observed.
C
1
3
t
proton was not observed. C NMR (100 MHz): d 20.8
CH ), 22.4 (CH ), 29.9 (CH adamantyl), 37.7 (Cq ada-
NMR (100 MHz): d 29.5 (CH ), 34.7 (Cq, Bu), 50.6
3
(
(CH –N), 57.2 (CH, CH-Fc), 64.7 (CH –O), 66.1 (CH),
3
3
2
2

a
R. M Moreno et al. / Tetrahedron: Asymmetry 17 (2006) 1089–1103
1101
6
1
7.5 (CH), 67.7 (CH), 68.3 (CH), 68.7 (CH), 87.1 (Cq, Fc),
18.4 (CH, Ar), 122.9 (Cq, Ar), 126.1 (CH, Ar), 126.6 (CH,
tilled benzaldehyde (67 ll, 0.66 mmol) and cyano-
trimethylsilane (0.19 ml, 1.45 mmol) were added to a cold
(ꢀ60 ꢁC), stirred solution of 6aB (59 mg, 0.14 mmol) and
of titanium tetra(isopropoxide) (40 ll, 0.13 mmol) in anhy-
drous dichloromethane (1.5 ml). After 63 h of stirring,
work-up and purification, 9 (73 mg) was isolated in 83%
yield and with a 86:14 er.
Ar), 137.0 (Cq, Ar), 157.0 (Cq, Ar, C–OH) ppm. MS (CI,
NH ) m/e: 408 (M+1, 26%), 229 (Mꢀ178, 100%). HRMS
3
(
CI) C H FeNO (M): calcd 407.1548, found 407.1553.
23 29 2
4
.4.3. 2-tert-Butyl-6-[((1S,2R)-1-ferrocenyl-2-hydroxypro-
pylamino)methyl]phenol 8bB. In a similar way, 70 mg
(
(
(
0.19 mmol) of 6bB was treated with sodium borohydride
14 mg, 0.37 mmol) and cerium(III) chloride heptahydrate
70 mg, 0.19 mmol) in methanol (2 ml, 90 min at room tem-
The enantiomeric purity of this compound was determined
in the following way. To a stirred solution of 9 (60 mg,
0.45 mmol) in dry pyridine (0.9 ml, 11 mmol), acetic anhy-
dride (0.6 ml, 0.9 mmol) was added via a syringe. After
15 h of stirring at room temperature (TLC monitoring),
the reaction mixture was diluted with ethyl acetate
(10 ml), washed with aqueous saturated ammonium chlo-
ride (3 · 10 ml) and brine (2 · 10 ml) and dried over mag-
nesium sulfate. Evaporation of the solvents under
perature) to afford 57 mg (73% yield) of the title compound
23
as a yellow solid. Mp: 118.8–119.5 ꢁC. ½aꢁ ¼ þ180:8 (c
D
0
1
.52, EtOH). IR (KBr): m
559, 1437, 1239, 1071, 822 cm . H NMR (200 MHz):
= 3313, 3091, 2960, 1654,
max
ꢀ
1 1
d 1.26 (d, J = 6.4 Hz, 3H, CH –CHOH), 1.44 (s, 9H,
3
J = 13.6 Hz, 1H, CH –OH), 4.10 (d, J = 13.6 Hz, 1H,
CH –OH), 4.11 (s, 1H, Fc), 4.17 (s, 5H, Fc), 4.21 (m,
2
(
2
3
· CH ), 3.39 (d, J = 2.8 Hz, CH-Fc), 3.88 (d,
3
23
vacuum afforded the levorotatory f½aꢁ ¼ ꢀ4:2 (c 1.2,
2
D
2
7
CHCl ); {lit. = ꢀ7.24 (c 2.3, CHCl )} acetate of 10 that
2
3
3
H, Fc), 4.29 (m, 2H), 6.73 (t, J = 7.6 Hz, 1H, Ar), 6.86
was analyzed by GC using a b-DEX 120 column at
140 ꢁC. tR(R) = 28.4 min, tR(S) = 31.7 min.
d, J = 6.0 Hz, 1H, Ar), 7.21 (dd, J = 7.8 Hz, J =
1
2
.0 Hz, 1H, Ar) ppm. The signals corresponding to the
1
3
OH and to the NH protons were not observed.
C
t
4.5.2.2. (S)-2-Hydroxy-2-(2-methoxyphenyl)acetonitrile.
According to the general procedure described above,
freshly distilled 2-methoxybenzaldehyde (82 ll, 0.67 mmol)
and cyanotrimethylsilane (0.20 ml, 1.47 mmol) were added
to a cold (ꢀ60 ꢁC), stirred solution of 6aB (60 mg,
NMR (50 MHz): d 20.4 (CH ), 29.5 (CH , Bu), 34.7 (Cq,
3
3
t
Bu), 51.4 (CH ), 60.6 (CH, CH-Fc), 67.3 (CH), 67.4
2
(
1
(
CH), 68.3 (CH), 68.6 (CH), 71.1 (CH), 88.8 (Cq, Fc),
18.3 (CH, Ar), 123.1 (Cq, Ar), 126.0 (CH, Ar), 126.6
CH, Ar), 136.8 (Cq, Ar), 157.0 (Cq, Ar, C–OH) ppm.
0.15 mmol) and of titanium tetra(isopropoxide) (40 ll,
0.13 mmol) in anhydrous dichloromethane (1.5 ml). After
70 h of stirring, work-up and purification, the title com-
MS (CI, NH ) m/e: 422 (M+1, 10%), 376 (Mꢀ45, 30%).
3
HRMS (CI) C H FeNO (M+1): calcd 422.1782, found
2
4
32
2
4
22.1783.
pound (66 mg) was isolated in 60% yield and with a
1
9
8
0:20 er (determined by F NMR of the corresponding
4.5. Catalytic asymmetric trimethylsilylcyanation of
aldehydes
23
29
Mosher ester). ½aꢁ ¼ ꢀ23:6 (c 1.40, CHCl ). {lit:
D
3
[
a] ((S), 87:23 er) = ꢀ23.8 (c 3.05, CHCl )].
D
3
4
.5.1. General procedure for the enantioselective addition of
cyanotrimethylsilane to aldehydes catalyzed by Schiff base–
titanium isopropoxide complexes. To a stirred solution of
the chiral Schiff base (0.22 mmol) in anhydrous dichloro-
methane (2 ml) under an argon atmosphere, titanium
tetra(isopropoxide) (60 ll, 0.20 mmol) was added via a syr-
inge. The resulting red-coloured solution was stirred at
room temperature for 1 h and cooled to ꢀ60 ꢁC. At this
point, aldehyde (1.0 mmol) and cyanotrimethylsilane
4
.5.2.3. (S)-2-Hydroxy-2-(3-methoxyphenyl)acetonitrile.
According to the general procedure described above,
freshly distilled 3-methoxybenzaldehyde (80 ll, 0.67 mmol)
and cyanotrimethylsilane (0.20 ml, 1.47 mmol) were added
to a cold (ꢀ60 ꢁC), stirred solution of 6aB (60 mg,
0
0
7
.15 mmol) and of titanium tetra(isopropoxide) (40 ll,
.13 mmol) in anhydrous dichloromethane (1.5 ml). After
0 h of stirring, work-up and purification, the title com-
(
0.29 ml, 2.2 mmol) were added sequentially via syringe.
pound (84 mg) was isolated in 85% yield and with a
0:30 er (determined by F NMR of the corresponding
After stirring at the same temperature for 64–68 h, the
solution was poured over a mixture of 1 M aqueous HCl
19
7
23
D
3b
Mosher ester). ½aꢁ ¼ ꢀ14:9 (c 1.40, CHCl ). {lit: [a]D
3
(
45 ml) and ethyl acetate (90 ml), and stirred vigorously
(
(R), 78:22 er) = +22.8 (c 1.5, CHCl )}.
3
at room temperature for 20–24 h. The resulting mixture
was extracted with ethyl acetate (3 · 25 ml) and the com-
bined extracts were washed with saturated aqueous sodium
bicarbonate (2 · 25 ml) and brine (2 · 25 ml), dried over
magnesium sulfate and evaporated under reduced pressure.
The residue was purified by column chromatography on
silica gel (eluent, hexane–ethyl acetate mixtures of increas-
ing polarity).
4
.5.2.4. (S)-2-Hydroxy-2-(4-methoxyphenyl)acetonitrile.
According to the general procedure described above,
freshly distilled 4-methoxybenzaldehyde (0.13 ml, 1.07 mmol)
and cyanotrimethylsilane (0.31 ml, 2.35 mmol) were added
to a cold (ꢀ60 ꢁC), stirred solution of 6aB (95 mg,
0
0
6
.23 mmol) and of titanium tetra(isopropoxide) (60 ll,
.21 mmol) in anhydrous dichloromethane (2.5 ml). After
3 h of stirring, work-up and purification, the title com-
4
.5.2. Enantioselective cyanotrimethylsilane addition to
pound (82 mg) was isolated in 47% yield and with a
2:38 er (determined by F NMR of the corresponding
aldehydes catalyzed by the titanium isopropoxide complex
of imine 6aB.
1
9
6
23
D
29
Mosher ester). ½aꢁ ¼ ꢀ21:7 (c 1.00, CHCl ). {lit: [a]D
4
.5.2.1. (S)-2-Hydroxy-2-phenylacetonitrile 9. Accord-
3
(
(S), 92:8 er) = ꢀ38.3 (c 1.86, CHCl )}.
ing to the general procedure described above, freshly dis-
3

a
1102
R. M Moreno et al. / Tetrahedron: Asymmetry 17 (2006) 1089–1103
4
.5.2.5.
(S)-2-Hydroxy-2-(4-methylphenyl)acetonitrile.
was isolated in 63% yield and with a 81:19 er (determined
1
9
According to the general procedure described above,
freshly distilled 4-methylbenzaldehyde (78 ll, 0.66 mmol)
and cyanotrimethylsilane (0.19 ml, 2.35 mmol) were added
to a cold (ꢀ60 ꢁC), stirred solution of 6aB (59 mg, 0.14
mmol) and of titanium tetra(isopropoxide) (40 ll, 0.13
mmol) in anhydrous dichloromethane (1.5 ml). After 64 h
of stirring, work-up and purification, the title compound
by23 F NMR of the corresponding Mosher ester).
3b
½aꢁ ¼ ꢀ7:8 (c 0.82, CHCl ). {lit: [a]D ((R), 92:8 er) =
D
3
+5.7 (c 1.3, CHCl )}.
3
4.5.3. Enantioselective cyanotrimethylsilane addition to
aldehydes catalyzed by the titanium isopropoxide complex
of imine 6bB.
(
(
67 mg) was isolated in 69% yield and with a 82:18 er
4.5.3.1.
(S)-2-Hydroxy-2-(2-methoxyphenyl)aceto-
1
9
determined by F NMR of the corresponding Mosher
nitrile. According to the general procedure described
above, freshly distilled 2-methoxybenzaldehyde (91 ll,
0.75 mmol) and cyanotrimethylsilane (0.22 ml, 1.65 mmol)
were added to a cold (ꢀ60 ꢁC), stirred solution of 6bB
(69 mg, 0.15 mmol) and of titanium tetra(isopropoxide)
(50 ll, 0.14 mmol) in anhydrous dichloromethane
(1.5 ml). After 62 h of stirring, work-up and purification,
the title compound (104 mg) was isolated in 85% yield
2
D
3
3b
ester). ½aꢁ ¼ ꢀ35:2 (c 1.70, CHCl ). {lit: [a]D ((R), 85:15
3
er) = +36.4 (c 1.1, CHCl )}.
3
4
.5.2.6.
(S)-2-Hydroxy-2-(4-cyanophenyl)acetonitrile.
According to the general procedure described above, a
solution of 4-cyanobenzaldehyde (96 mg, 0.73 mmol) in
anhydrous dichloromethane (0.5 ml) and cyanotrimethylsi-
lane (0.21 ml, 1.61 mmol) was added to a cold (ꢀ60 ꢁC),
stirred solution of 6aB (65 mg, 0.16 mmol) and of titanium
tetra(isopropoxide) (50 ll, 0.15 mmol) in anhydrous
dichloromethane (1.5 ml). After 64 h of stirring, work-up
and purification, the title compound (89 mg) was isolated
1
9
and with a 77:23 er (determined by F NMR of the corre-
sponding Mosher ester).
4.5.3.2.
(S)-2-Hydroxy-2-(4-methylphenyl)acetonitrile.
According to the general procedure described above,
freshly distilled 4-methylbenzaldehyde (82 ll, 0.69 mmol)
and cyanotrimethylsilane (0.20 ml, 1.52 mmol) were added
to a cold (ꢀ60 ꢁC), stirred solution of 6bB (64 mg, 0.15
mmol) and of titanium tetra(isopropoxide) (40 ll,
1
9
in 77% yield and with a 58:42 er (determined by
F
23
NMR of the corresponding Mosher ester). ½aꢁ ¼ ꢀ11:2
D
2
9
(
1
c 0.91, CHCl ). {lit: [a] ((S), 65:35 er) = ꢀ11.2 (c
3
D
.00, CHCl )}.
3
0.13 mmol) in anhydrous dichloromethane (1.5 ml). After
4
.5.2.7.
(S)-2-Hydroxy-2-(2-fluorophenyl)acetonitrile.
62 h of stirring, work-up and purification, the title com-
pound (56 mg) was isolated in 55% yield and with a
79:21 er (determined by F NMR of the corresponding
Mosher ester).
According to the general procedure described above,
freshly distilled 2-fluorobenzaldehyde (76 ll, 0.72 mmol)
and cyanotrimethylsilane (0.20 ml, 1.58 mmol) were added
to a cold (ꢀ60 ꢁC), stirred solution of 6aB (65 mg, 0.16
mmol) and of titanium tetra(isopropoxide) (50 ll, 0.15
mmol) in anhydrous dichloromethane (1.5 ml). After 64 h
of stirring, work-up and purification, the title compound
1
9
Note added in proof
(
76 mg) was isolated in 70% yield and with a 73:27
Very recently, tridentate Schiff base ligands arising from
enantiopure epoxyalcohols have been prepared and eval-
uated in the titanium-catalyzed trimethylsilyl cyanide
addition to aldehydes: Rodr ´ı guez, B.; Past o´ , M.; Jimeno,
C.; Peric a` s, M. A. Tetrahedron: Asymmetry 2006, 17,
151–160.
1
9
er (determined by F NMR of the corresponding Mosher
2
D
3
30
ester). ½aꢁ ¼ ꢀ11:6 (c 0.93, CHCl ). {lit: [a]D ((R), 92:8
3
er) = +21.8 (c 3.6, CHCl )}.
3
4
.5.2.8. (S)-2-Hydroxy-(E)-3-pentenenitrile. According
to the general procedure described above, freshly distilled
E)-crotonaldehyde (76 ll, 0.86 mmol) and cyanotrimeth-
ylsilane (0.25 ml, 1.89 mmol) were added to a cold
(
Acknowledgements
(
ꢀ60 ꢁC), stirred solution of 6aB (74 mg, 0.19 mmol) and
We gratefully acknowledge the financial support from
of titanium tetra(isopropoxide) (50 ll, 0.15 mmol) in anhy-
drous dichloromethane (2.0 ml). After 41 h of stirring,
work-up and purification, the title compound (63 mg)
was isolated in 76% yield and with a 73:27 er (determined
Ministerio de Ciencia
y
Tecnolog ´ı a (DGI, project
BQU2003-03426). R.M. and M.R. thank the Generalitat
de Catalunya (DURSI) for predoctoral fellowships. We
are grateful to Professor V. K. Aggarwal (University of
Bristol) for a generous gift of (1R,2S)-2-azido-2-ferrocen-
yl-1-phenylethanol.
1
9
by23 F NMR of the corresponding Mosher ester).
3b
½
aꢁ ¼ þ11:1 (c 0.21, CHCl ). {lit: [a]D ((R), 94:6 er) =
D
3
ꢀ
35.7 (c 0.3, CHCl )}.
3
4
.5.2.9.
(S)-2-Hydroxy-3-methyl-3-butenenitrile.
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