A high yielding one-pot method for the preparation of salen ligands

Article abstract of DOI:10.1016/j.tetlet.2005.03.193

Phenols are converted to salicylaldehydes with paraformaldehyde, MgCl ₂-Et₃N in THF, and subsequently treated with (+)-(R,R)-1,2-diammoniumcyclohexane mono-(+)-tartrate salt affording the corresponding salen ligands in high yields. The reactions are conveniently carried out as a one-pot procedure.

Full text of DOI:10.1016/j.tetlet.2005.03.193

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3829–3830
A high yielding one-pot method for the preparation of salen ligands
Trond Vidar Hansena,* and Lars Skattebølb
aSchool of Pharmacy, Department of Chemistry, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway
bDepartment of Chemistry, University of Oslo, PO Box 1033 Blindern, N-0315 Oslo, Norway
Received 20 January 2005; revised 21 March 2005; accepted 29 March 2005
Available online 12 April 2005
Abstract—Phenols are converted to salicylaldehydes with paraformaldehyde, MgCl2–Et3N in THF, and subsequently treated with
(+)-(R,R)-1,2-diammoniumcyclohexane mono-(+)-tartrate salt affording the corresponding salen ligands in high yields. The reac-
tions are conveniently carried out as a one-pot procedure.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Manganese(III) chloride complexed with the salen
ligand (R,R)-N,N0-bis(3,5-di-tert-butyl-salicylidene)-1,2-
cyclohexanediamine (1), the Jacobsen catalyst, is among
the most versatile catalysts for the preparation of homo-
chiral epoxides from alkenes.1 Salens are also used as
ligands for other catalysts of importance in asymmetric
synthesis.1 Jacobsen and Larrow2 have published a de-
tailed procedure for the preparation of ligand 1, starting
from 2,4-di-tert-butylphenol (2). In the first step the
phenol was transformed into the corresponding 2,5-di-
tert-butylsalicylaldehyde (3), which in a separate step
was condensed with (R,R)-1,2-diammoniumcyclohexane
mono-(+)-tartrate salt (4)3 to give the ligand 1. The
formylation is the critical step of the reaction sequence.
The Duff reaction gave a better yield of the salicylalde-
hyde than either the tin tetrachloride catalyzed formyl-
ation or the Reimer–Tiemann reaction;4 however, the
overall yield of the ligand 1 was only in the range of
35–45%, which certainly leaves room for improvement.
We have recently reported a method for the selective
ortho-formylation of phenols.5 The method consists of
heating under reflux a mixture of a phenol, paraformal-
dehyde, anhydrous magnesium dichloride, and triethyl-
amine in a solvent. From alkyl- and halogen-sub-
stituted phenols, in particular, the corresponding salicyl-
aldehydes were obtained in excellent yields. Applying
this simple procedure to the phenol 2 using THF as
solvent, the salicylaldehyde 3 was obtained in 85% yield,
which is almost twice the yield reported from the Duff
reaction.4 However, it was later proved unnecessary to
actually isolate the aldehyde 3, but rather treat it directly
with the salt 4 (Scheme 1).
According to this one-pot procedure, an aqueous etha-
nol solution of 4 and potassium carbonate was added
at ambient temperature to the mixture from the formyl-
ation reaction. After 4 h of heating at 80 ꢁC the alde-
hyde had been consumed. Recrystallization of the
Scheme 1.
Keywords: ortho-Formylation of phenols; Jacobsen ligand; Salen ligands.
*
Corresponding author. Tel.: +47 22857450; fax: +47 22855947; e-mail: t.v.hansen@farmasi.uio.no
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.193

3830
T. V. Hansen, L. Skattebøl / Tetrahedron Letters 46 (2005) 3829–3830
6. Preparation of 1: to a stirred suspension of 2,4-di-tert-
butylphenol (2) (4.12 g, 20 mmol), anhydrous MgCl2
(3.81 g, 40 mmol) and dry paraformaldehyde (1.32 g,
44 mmol) in dry THF (80 mL), kept at ambient tempera-
ture, was added dropwise dry Et3N (4.05 g, 40 mmol). The
green-colored reaction mixture was then heated to gentle
reflux for 2 h. GLC analysis showed complete conversion of
starting materials to 3,5-di-tert-butyl salicylaldehyde. A
solution of (R,R)-1,2-diammoniumcyclohexane mono-(+)-
tartrate salt 4 (2.65 g, 10 mmol) and K2CO3 (3.12 g,
22.5 mmol) in ethanol–water (1:1, 30 mL) was added
dropwise at ambient temperature. After addition was
complete, the reaction mixture was heated for 4 h at
80 ꢁC. The yellow-colored reaction mixture was cooled and
added to water. The product was extracted with CH2Cl2
(3 · 100 mL), the combined organic fractions were washed
with water (50 mL), brine (2 · 50 mL), and dried (MgSO4).
Removal of solvents afforded a yellow solid that was
recrystallized from acetone (1:20 w/v) to give (ꢀ)-(R,R)-
N,N0-bis(3,5-di-tert-butyl)-salicylidene)-1,2-cyclohexanedi-
amine (1) as a yellow powder (84% yield), mp 201–204 ꢁC;
lit.4 200–203 ꢁC; 1H NMR (300 MHz): d 13.74 (s, 2H), 8.33
(s, 2H), 7.31 (d, J = 2.1 Hz, 2H), 7.02 (d, J = 2.1 Hz, 2H),
3.70–3.30 (m, 2H), 2.00–1.30 (m, 6H), 1.45 (s, 20H), 1.25 (s,
18H); 13C NMR (75 MHz): 165.9, 158.2, 139.9, 136.4,
126.7, 126.2, 117.9, 72.5, 35.2, 34.1, 33.4, 29.6,
residue from acetone afforded the salen ligand 1 in 84%
yield, based on the phenol 2, exhibiting spectral data in
accordance with those reported.4 Experimental details
for the preparation of 1 are given below.6
The usefulness of this one-pot method is not limited to
the preparation of the salen ligand 1. The ligands 5, 6,
and 74 were prepared from the corresponding phenols
in 85%, 93%, and 80% yields, respectively.
In conclusion, using this simple one-pot procedure,
salen ligands are available from the respective phenols
in considerably better overall yields than those previ-
ously reported.
References and notes
1. Larrow, J. R.; Jacobsen, E. N. Top. Organomet. Chem.
2004, 6, 123–152.
2. Jacobsen, E. N.; Larrow, J. R. Org. Synth. 1998, 75, 1–11.
3. Gasbøl, F.; Steenbøl, P.; Sørensen, B. S. Acta Chem. Scand.
1972, 26, 3605–3611.
4. Larrow, J. F.; Jacobsen, E. N.; Gao, Y.; Hong, Y.; Nie, X.;
Zepp, C. M. J. Org. Chem. 1994, 59, 1939–1942.
5. Hofsløkken, N. U.; Skattebøl, L. Acta Chem. Scand. 1999,
53, 258–262.
22
22
24.4; ½aꢁD ꢀ312 (c 1.0, CH2Cl2), lit.4 ½aꢁD ꢀ315 (c 1.0,
CH2Cl2).