Single-step synthesis of salans and substituted salans by Mannich condensation

Article abstract of DOI:10.1016/S0040-4039(01)01264-3

A convenient route for the synthesis of a variety of salan-type compounds is introduced. The synthesis is based on a single-step Mannich condensation between readily available starting materials: primary or secondary amines, formaldehyde and substituted phenols. This methodology is suitable for the preparation of chiral salans as well, which may find applications in asymmetric catalysis.

Full text of DOI:10.1016/S0040-4039(01)01264-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6405–6407
Single-step synthesis of salans and substituted salans by
Mannich condensation
Edit Y. Tshuva, Natalie Gendeziuk and Moshe Kol*
School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv 69978, Israel
Received 21 May 2001; accepted 12 July 2001
Abstract—A convenient route for the synthesis of a variety of salan-type compounds is introduced. The synthesis is based on a
single-step Mannich condensation between readily available starting materials: primary or secondary amines, formaldehyde and
substituted phenols. This methodology is suitable for the preparation of chiral salans as well, which may find applications in
asymmetric catalysis. © 2001 Elsevier Science Ltd. All rights reserved.
The continuing search for new ligand systems for tran-
sition metals has drawn considerable interest to chelat-
ing amino and hydroxy compounds.1 Compounds of
the salen family have been studied extensively for many
purposes and applied mostly in catalysis.2–4 Salens are
usually synthesized by condensing salicyl aldehydes and
diamino compounds. Salan compounds (reduced
salens)5–9 have also been investigated for similar pur-
poses. They are usually synthesized by reducing the
corresponding salens to give the tetrahydrosalens, con-
sisting of two secondary amine groups.5–9 Previously,
the preparation of N,N%-disubstituted salans required
additional steps of substitution on the salans,10–12 or
alternatively, relied on reacting secondary amines with
salicylaldehydes, followed by reduction.13,14 We intro-
duce herein, a single-step synthetic procedure enabling
the preparation of a variety of salan compounds, as
well as N,N%-disubstituted salans in high yields, which
may serve as ligands for metal-based catalysts, from
readily available highly versatile starting materials.15
Based on this procedure, chiral compounds may be
prepared as well.12
These N,N%-bis(2-hydroxyarylmethyl)-diamine com-
pounds are synthesized by a Mannich condensation of
substituted phenols, formaldehyde and diamines
(Scheme 1). Thus, heating a solution of 10 mmol of
N,N%-dimethylethylenediamine, 2 equiv. of 2,4-di-tert-
butylphenol and an excess of 37% aqueous formalde-
hyde (10 equiv.) in 10 ml of methanol at reflux for 2 h,
gave 1 (Scheme 1) in 88% yield as a colorless solid, that
crystallized out of the reaction mixture, and was iso-
lated by filtration. The other disubstituted salans
R''
R''
R''
2
HO
OH
HO
RHN -R'-NHR + excess HCHO + 2
H
N R' N
1
R
R
1: R = Me, R' = CH2CH2, R'' = 3,5-di-tert-butyl, 88% yield
2: R = Bn, R' = CH2CH2, R'' = 3,5-di-tert-butyl, 96% yield
3: R = Et, R' = CH2CH2, R'' = 3,5-di-tert-butyl, 71% yield
4: R = Me, R' = CH2CH2, R'' = 3,5-dimethyl, 82% yield
5: R = Me, R' = CH2CH2, R'' = 4,5-dimethyl, 88% yield
6: R = H, R' = CH2CH2, R'' = 3,5-di-tert-butyl, 90% yield
7: R = Me, R' = CH2CH2CH2, R'' = 3,5-di-tert-butyl, 100% yield
8: R = H, R' = CH2CH2CH2, R'' = 3,5-di-tert-butyl, 87% yield
Scheme 1.
Keywords: salans; substituted salans; Mannich condensation; chiral compounds.
* Corresponding author. Tel: +972-3-640-7392; fax: +972-3-640-9293; e-mail: moshekol@post.tau.ac.il
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01264-3

6406
E. Y. Tshu6a et al. / Tetrahedron Letters 42 (2001) 6405–6407
HO
OH
t-Bu
t-Bu
t-Bu
HO
NH HN
HO
+ excess HCHO + 2
OH
K2CO3
-OOC
+H3N
COO-
+
·
NH3
H
t-Bu
90% yield
t-Bu t-Bu
R,R
R,R
Scheme 2.
described in Scheme 1 were obtained cleanly by
analogous reactions in 70–100% yields.† This methodol-
ogy carries a further advantage; as the substituted
salicylaldehydes employed in previous syntheses are
replaced by substituted phenols and formaldehyde, the
scope of possible salans is broadened since a large
variety of substituted phenols are commercially
available.
contamination by tertiary amines. These compounds
may be potentially used directly as ligands, or serve as
starting materials for hexadentate ligands,16 upon fur-
ther substitution on the secondary nitrogen atoms.
We attempted the synthesis of chiral compounds, which
may be employed as ligands in chiral complexes for use
in asymmetric catalysis.17 Rac-trans-1,2-diaminocyclo-
hexane is commercially available, and is often used for
the preparation of chiral salen compounds.18 In order
to avoid tedious separation of the optically active
diamine, we attempted the direct use of the tartrate salt
used for the resolution of one enantiomer of the
diamine from the racemic mixture. Thus, the (R,R)-1,2-
diammoniumcyclohexane mono-(+)-tartrate was pre-
pared according to a known procedure,18 and 4.0 mmol
of the salt were mixed with 2 equiv. of potassium
carbonate in 5 ml of water, and stirred until dissolution
was reached. Addition of 20 ml of ethanol caused
precipitation of the salts, while heating the mixture to
60°C resulted in complete dissolution. 2 Equiv. of 2,4-
di-tert-butylphenol and 10 equiv. of 37% aqueous
formaldehyde were dissolved in 7 ml of ethanol and
then added dropwise, and after heating the reaction
mixture to reflux for 2.5 h, the crude product precipi-
tated in 90% yield and was isolated by filtration
(Scheme 2). The product may be further purified by
flash chromatography on a silica column, using chloro-
form as the eluting solvent. The purified compound has
a specific rotation of [h]2D3=−35 (c=0.6, CH2Cl2).‡
The bridging unit between the two nitrogen atoms, the
substituents on the amine group, and the substitution
pattern on the phenols may be varied, thus this simple
methodology gives rise to a variety of salans (Scheme
1). The bulk of the aromatic ring substituents is
expected to play a significant role in the reactivity of
the resulting metal complexes by directing incoming
substrates. Similar effects may arise from varying the
nitrogen substituents. The length of the bridging unit
between the nitrogen atoms may also be designed to fit
binding to a particular metal, by proper choice of the
diamine.
Interestingly, this methodology was found to be suc-
cessful for primary amines as well (Scheme 1, entries 6,
8). Despite our concerns regarding the reaction selectiv-
ity, the desired unsubstituted salans formed, crystallized
out of the reaction mixture, and were isolated by
filtration in similar yields to those obtained for the
substituted compounds. NMR analysis indicated no
This synthetic route is signified by its high convenience,
as well as the wide scope of ligands that may be
prepared. The starting materials are inexpensive and
versatile. Furthermore, the preparation of chiral com-
pounds is of great significance, as chiral ligands may
lead to chiral complexes inducing asymmetric catalysis
of various organic reactions.17 We are currently study-
ing the application of such chiral complexes in asym-
metric catalysis as well as the application of achiral
ligands in olefin polymerization catalysis and tacticity
induction.15
† 1H NMR of achiral compounds (CDCl3, 200 MHz): Compound 2:
l 7.19 (m, 12H, ArOH and C6H5), 6.79 (d, J=1.9 Hz, 2H, ArOH),
3.65 (s, 4H, CH2), 3.49 (s, 4H, CH2), 2.67 (s, 4H, CH2), 1.41 (s,
18H, C(CH3)3), 1.26 (s, 18H, C(CH3)3). Compound 3: l 7.19 (d,
J=2.3 Hz, 2H, ArOH), 6.80 (d, J=2.2 Hz, 2H, ArOH), 3.70 (s, 4H,
CH2), 2.66 (s, 4H, CH2), 2.55 (q, J=7.1 Hz, 4H CH2CH3), 1.39 (s,
18H, C(CH3)3), 1.27 (s, 18H, C(CH3)3), 1.00 (t, J=7.1 Hz, 6H,
CH2CH3). Compound 5: l 6.69 (s, 2H, ArOH), 6.63 (s, 2H, ArOH),
3.63 (s, 4H, CH2), 2.64 (s, 4H, CH2), 2.27 (s, 6H, CH3), 2.19 (s, 6H,
CH3), 2.14 (s, 6H, CH3). Compound 6:13 l 10.69 (br, 2H, OH), 7.22
(d, J=2.3 Hz, 2H, ArOH), 6.83 (d, J=2.2 Hz, 2H, ArOH), 3.88 (s,
4H, CH2), 3.52 (s, 2H, NH), 2.99 (s, 4H, CH2), 1.42 (s, 18H,
C(CH3)3), 1.27 (s, 18H, C(CH3)3). Compound 7: l 7.11 (s, 2H,
ArOH), 6.73 (s, 2H, ArOH), 3.56 (s, 4H, CH2), 2.37 (t, J=7.6 Hz,
4H, NCH2), 2.18 (s, 6H, NCH3), 1.69 (quin, J=7.6, 2H, CH2), 1.32
(s, 18H, C(CH3)3), 1.19 (s, 18H, C(CH3)3). Compound 8:13 l 7.22
(d, J=2.4 Hz, 2H, ArOH), 6.86 (d, J=2.3 Hz, 2H, ArOH), 3.76 (s,
4H, CH2), 3.46 (s, 2H, NH), 2.71 (m, 4H, CH2), 1.76 (t, J=6.0, 2H,
CH2), 1.42 (s, 18H, C(CH3)3), 1.28 (s, 18H, C(CH3)3). For com-
pounds 1,4 see Ref. 15.
‡ 1H NMR of (R,R)-N,N%-bis(3,5-di-tert-butylsalicyl)-1,2-cyclohex-
anediamine (CDCl3, 200 MHz): l 7.18 (d, J=2.1, 2H, ArOH), 6.79
(d, J=2.0, 2H, ArOH), 4.15 (d, J=13.6, 2H, ArCH2), 3.53 (s, 2H,
NH), 3.46 (d, J=13.6, 2H, ArCH2), 2.34 (m, 2H), 2.02 (m, 2H),
1.82 (m, 3H), 1.34–1.24 (m, 3H), 1.40 (s, 18H, C(CH3)3), 1.24 (s,
18H, C(CH3)3). [h]2D3 −35 (c=0.6, CH2Cl2).

E. Y. Tshu6a et al. / Tetrahedron Letters 42 (2001) 6405–6407
6407
Acknowledgements
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