Efficient tetrahydrosalen synthesis from Mannich-type bases

Article abstract of DOI:10.1081/SCC-120039502

Synthesizing a variety of tetrahydrosalens from hydrolyzing 1,3-bis (2′-hydroxy-5′-substituted-benzyl)imidazolidines with hydrochloric acid is described. Further reaction of such tetrahydrosalens with aldehydes yielded 2-substituted-1,3-bis(2′-hydroxy-5′-substituted-benzyl) imidazolidines.

Full text of DOI:10.1081/SCC-120039502

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Efficient Tetrahydrosalen
Synthesis from Mannich‐Type
Bases
Augusto Rivera a , Rodolfo Quevedo a , Miguel A.
Navarro a & Mauricio Maldonado a
a Departamento de Química, Universidad Nacional
de Colombia, Apartado Aéreo 14490, Ciudad
Universitaria, Bogotá, Colombia
Published online: 10 Jan 2011.
To cite this article: Augusto Rivera , Rodolfo Quevedo , Miguel A. Navarro
& Mauricio Maldonado (2004) Efficient Tetrahydrosalen Synthesis from
Mannich‐Type Bases, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 34:13, 2479-2485, DOI: 10.1081/
SCC-120039502
To link to this article: http://dx.doi.org/10.1081/SCC-120039502
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 13, pp. 2479–2485, 2004
Efficient Tetrahydrosalen Synthesis
from Mannich-Type Bases
*
Augusto Rivera, Rodolfo Quevedo, Miguel A. Navarro,
and Mauricio Maldonado
´
Departamento de Quımica, Universidad Nacional de Colombia,
´
Ciudad Universitaria, Bogota, Colombia
ABSTRACT
Synthesizing a variety of tetrahydrosalens from hydrolyzing 1,3-bis
(20-hydroxy-50-substituted-benzyl)imidazolidines with hydrochloric acid
is described. Further reaction of such tetrahydrosalens with alde-
hydes yielded 2-substituted-1,3-bis(20-hydroxy-50-substituted-benzyl)
imidazolidines.
Key Words: Tetrahydrosalen; Mannich-type bases; Ethylenediamine;
Formaldehyde.
*
´
Correspondence: Augusto Rivera, Departamento de Quımica, Universidad Nacional
´ ´
de Colombia, Apartado Aereo 14490, Ciudad Universitaria, Bogota, Colombia;
E-mail: ariverau@unal.edu.co.
2479
DOI: 10.1081/SCC-120039502
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

2480
Rivera et al.
INTRODUCTION
The continuing search for new ligand systems for transition metals has
drawn considerable interest to chelating amino and hydroxy compounds.
Compounds from the salen family have been extensively studied for many
purposes and applied mostly in catalysis.[1] Tetrahydrosalens have also been
investigated for the potential use as achiral ligand that can adopt asymmetric
conformations and can participate in enantioselective catalysis transferring
asymmetry from the catalyst to the substrate.[2–5] Previous syntheses of
N,N0-bis(2-hydroxybenzyl)ethylenediamine compounds (tetrahydrosalens)
have involved isolation of the salen intermediate and reduction with NaBH4
or LiAlH4, resulting in lower yields.[6] Other procedures employ the reductive
amination of N-N0-dimethylethylenediamine with NaBH3(CN).[7] Tshuva
et al. recently published a new method for synthesizing tetrahydrosalens in
a single stage via Mannich condensation from primary or secondary diamine,
formaldehyde, and a substituted phenol.[1]
In a previous paper,[8] we reported that 1,3-bis(20-hydroxy-50-substituted-
benzyl)imidazolidines reacted with benzaldehyde and p-methoxybenzaldehyde
affording 2t-substituted-1r,3c-bis(20-hydroxy-50-substituted-benzyl)imidazo-
lidines as the main reaction product and proposed a mechanism which
involves the possible formation of N,N0-bis(5-substituted-2-hydroxybenzyl)
ethylenediamine as intermediate. It should be mentioned that the afore-
mentioned reaction failed when m-nitrobenzaldehyde and salicyaldehyde
were used and no transformation was observed; thus reaction with other
aldehydes or a ketone was chosen as the basis for the work reported in
this article. These results encouraged us to develop a general method for
synthesizing N,N0-bis(2-hydroxybenzyl)ethylenediamine tetrahydrosalens.
To test this method, we prepared 2a–e from imidazolidines 1a–e and
carried out reactions to obtain substituted tetrahydrosalens not only with
m-nitrobenzaldehyde, salicylaldehyde, benzaldehyde, and p-methoxybenz-
aldehyde but also with other carbonyl compounds such as furfural and
acetone. In all cases, 2-substituted-1,3-bis-(20-hydroxy-50-substituted-benzyl)
imidazolidines 3a–f were obtained with excellent yield.
EXPERIMENTAL
1H NMR spectra were measured on a Brucker AC-500 spectrometer opera-
ting at 500 MHz. In all cases, CDCl3 was used with TMS as the internal standard.
Melting points were determined with a electrothermal 9100 melting point appar-
atus and are uncorrected. The 1,3-bis(20-hydroxybenzyl)imidazolidines were
prepared as described[9] from phenols and 1,3,6,8-tetraazatricyclo[4.4.1.13,8
]

Tetrahydrosalen Synthesis from Mannich-Type Bases
2481
dodecane (TATD), which was prepared as described[10] from ethylenediamine
and formaldehyde and was further purified by recrystallisation from benzene.
All new compounds gave satisfactory elemental analysis.
General Procedure for the Synthesis of N,N0-bis
(2-Hydroxybenzyl)ethylenediamines 2a–e
A 10% hydrochloric acid (10 mL) was added to a 1,3-bis(20-hydroxy-50-
substituted-benzyl)imidazolidine 1 (3.0 mmol) in 1,4-dioxane (2 mL) solution;
the resulting mixture was stirred until a precipitate appeared. The product was
filtered off and washed with 1,4-dioxane. The N,N0-bis(2-hydroxybenzyl)ethyl-
enediamine hydrochloride obtained from the foregoing was dissolved in
methanol (5 mL). A 10% aqueous ammonia solution (10 mL) was added
and the mixture was stirred until a precipitate appeared. The N,N0-bis(2-hydro-
xybenzyl)ethylenediamine 2 was filtered and washed with water. Melting
points and yields are given in Table 1.
1H NMR: N,N0-bis(2-hydroxy-5-chlorobenzyl)ethylenediamine 2a d:
2.95 (s, 4H, CH2), 3.97 (s, 4H, Ar-CH2), 6.79 (d, 2H, H-C30), 6.95 (d, 2H,
H-C50), 7.14 (dd, 2H, H-C40); Anal. Calcd for C16H18Cl2N2O2: C, 56.26;
N, 8.20; H, 5.27; Cl, 20.78. Found: C, 56.30; N, 8.28; H, 5.20; Cl, 20.82.
N,N0-bis(2-Hydroxy-benzyl)ethylenediamine 2b d: 2.85 (s, 4H, CH2), 3.99
(s, 4H, Ar-CH2), 6.78 (td, 2H, H-C50), 6.83 (dd, 2H, H-C30), 6.98 (dd, 2H,
H-C60), 7.17 (td, 2H, H-C40). N,N0-bis(2-Hydroxy-3-methylbenzyl)ethylene-
diamine 2c d: 2.21 (s, 6H, CH3), 2.84 (s, 4H, CH2), 3.97 (s, 4H, Ar-CH2),
6.70 (t, 2H, H-C50), 6.83 (dd, 2H, H-C60), 7.05 (dd, 2H, H-C40); Anal. Calcd
for C18H24N2O2: C, 71.90; N, 9.32; H, 7.98. Found: C, 71.96; N, 9.37; H,
7.93. N,N0-bis(2-Hydroxy-4-methylbenzyl)ethylenediamine 2d: 2.27 (s, 6H,
CH3), 2.90 (s, 4H, CH2), 3.60 (s, 4H, Ar-CH2), 6.70 (d, 2H, H-C30), 6.60
(d, 2H, H-C60), 6.80 (dd, 2H, H-C50); Anal. Calc. for C18H24N2O2: C,
71.90; N, 9.32; H, 7.98. Found: C, 71.94; N, 9.34; H, 7.97. N,N0-bis
Table 1. Tetrahydrosalen yield from 1,3-bis(20-hydroxybenzyl)
imidazolidines 1.
Product
M.p. found/lit. (8C)
Yield (%)
2a
2b
2c
2d
2e
146
118/117[5]
129
90
87
71
83
89
151
140

2482
Rivera et al.
(2-Hydroxy-5-methylbenzyl)ethylenediamine 2e: 2.23 (s, 6H, CH3), 2.96
(s, 4H, CH2), 3.87 (s, 4H, Ar-CH2), 6.75 (d, 2H, H-C30), 6.99 (dd, 2H,
H-C40), 6.77 (d, 2H, H-C60); Anal. Calc. for C18H24N2O2 : C, 71.90; N, 9.32;
H, 7.98. Found: C, 71.96; N, 9.35; H, 7.95.
General Procedure for the Synthesis of 2-Substituted-1,3-bis
(20-hydroxy-50-chlorobenzyl)imidazolidines 3a–f
As stated in Section 1, either an aldehyde or a ketone (2.9 mmol) was
added to an ethylenediamine 2 (1.0 g, 2.9 mmol) in benzene (5 mL) solution
(in a well-ventilated fume cupboard). The reaction mixture was heated until
reflux occurred, product forming at different times depending on reagent
used; reaction was monitored by TLC. A resinous solid was obtained after
removing solvent at reduced pressure (20 mm Hg). The product was purified
by column chromatography on silica gel eluted with benzene : ethyl acetate
(8 : 2) mixture. Table 2 shows melting points, reaction time, and yields.
1H NMR: 2t-phenyl-1r,3c-bis(20-hydroxy-50-chlorobenzyl)imidazolidine
3a d: 2.68 (td, 2H, H-C4, H-C5), 3.34 (td, 2H, H-C4, H-C5), 3.30 (d, 2H,
Ar-CH2), 3.96 (d, 2H, Ar-CH2), 3.80 (s, 1H, H-C2), 6.70 (d, 2H, H-C30), 6.92
(d, 2H, H-C60), 7.08 (dd, 2H, H-C40), 7.46 (s, SH, H-C200, 300, 400, 500, 600);
2t-(200-hydroxyphenyl)-1r,3c-bis(20-hydroxy-50-chlorobenzyl)imidazolidine 3b
d: 2.65 (td, 2H, H-C4, H-C5), 3.27 (td, 2H, H-C4, H-C5), 3.35 (d, 2H,
Ar-CH2), 4.06 (d, 2H, Ar-CH2), 3.95 (s, 1H, H-C2), 6.76 (d, 2H, H-C30),
6.89 (m, 2H, H-C500, H-C600), 6.99 (d, 2H, H-C60), 7.09 (dd, 2H, H-C40),
7.16 (dd, 1H, H-C300), 7.22 (dd, 1H, H-C400); Anal. Calcd for C23H22Cl2N2O3:
C, 62.02; N, 6.29; H, 4.94; Cl, 15.92. Found: C, 62.13; N, 6.33; H, 4.91; Cl,
15.96. 2t-(300-Nitrophenyl)-1r,3c-bis(20-hydroxy-50-chlorobenzyl)imidazolidine
3c d: 2.75 (td, 2H, H-C4, H-C5), 3.40 (td, 2H, H-C4, H-C5), 3.47 (d, 2H,
Table 2. Reaction of N,N0-bis(2-hydroxy-5-chlorobenzyl)ethylenediamine 2 with
aldehydes and ketones.
M.p. found/
lit. (8C)
Time
(hr)
Yield
(%)
Carbonyl compound
Product
Benzaldehyde
Salicylaldehyde
m-Nitrobenzaldehyde
p-Methoxybenzaldehyde
Furfural
3a
3b
3c
3d
3e
3f
175/173–175[8]
169
6
14
36
2
91
78
161
187/187–189[8]
178
63
93
48
0.5
755
94
Acetone
181

Tetrahydrosalen Synthesis from Mannich-Type Bases
2483
Ar-CH2), 3.92 (d, 2H, Ar-CH2), 3.97 (s, 1H, H-C2), 6.65 (d, 2H, H-C30), 6.92
(d, 2H, H-C60), 7.65 (t, 1H, H-C50), 7.88 (d, 1H, H-C600), 8.25 (m, 2H, H-C400,
H-C200), 9.48 (s, 2H, OH). 2t-(400-Methoxyphenyl-1r,3c-bis(20-hydroxy-
50-chlorobenzyl)imidazolidine 3d d: 2.65 (td, 2H, H-C4, H-C5), 3.32 (td, 2H,
H-C4, H-C5), 3.27 (d, 2H, Ar-CH2), 3.98 (d, 2H, Ar-CH2), 3.75 (s, 1H,H-C2),
6.71 (d, 2H, H-C30), 6.92 (d, 2H, H-C60), 6.97 (d, 2H, H-C300, 500), 7.08 (dd,
2H, H-C40), 7.41 (d, 2H, H-C200, 600), 3.80 (s, 3H, O–CH3). 2t-furyl-
1r,3c-bis(20-Hydroxy-50-chlorobenzyl)imidazolidine 3e d: 2.78 (td, 2H,
H-C4, H-C5), 3.25 (td, 2H, H-C4, H-C5), 3.42 (d, 2H, Ar-CH2), 4.00 (d, 2H,
Ar-CH2), 4.20 (s, 1H, H-C2), 6.38 (s, 1H, H-C400), 6.50 (s, 1H, H-C300), 6.75
(d, 2H, H-C30), 6.92 (d, 2H, H-C60), 7.15 (dd, 2H, H-C40), 7.55 (s, 1H,
H-C500), 9.8 (s, 2H, OH); Anal. Calcd for C21H20Cl2N2O3: C, 60.10; N, 6.67;
H, 4.77; Cl, 16.91. Found: C, 60.07; N, 6.68; H, 4.75; Cl, 16.94. 2,2-Dimethyl-
1,3-bis(20-hydroxy-50-chlorobenzyl)imidazolidine 3f d: 1.35 (s, 6H, H-Cl00,
H-C200), 2.85 (s, 4H, H-C4, H-C5), 3.82 (s, 4H, Ar-CH2), 6.75 (d, 2H, H-C30),
6.98 (d, 2H, H-C60), 7.12 (dd, 2H, H-C40). Anal. Calcd for C19H22Cl2N2O2:C,
59.80; N, 7.34; H, 5.76; Cl, 18.59. Found: C, 59.77; N, 7.33; H, 5.79; Cl, 18.61.
RESULTS AND DISCUSSION
As mentioned above, acid hydrolysis of Mannich type bases such as
1,3-bis(20-hydroxybenzyl)-imidazolidine 1a–e synthesized according to the
cited methodology,[9] leads to tetrahydrosalens 2a–e, respectively (Sch. 1).
These results show that the nature and position of substituents in the
aromatic ring do not influence the course of the reaction, making this a very
versatile method for producing unsubstituted tetrahydrosalens with good
yield (Table 1). 1,3-bis(20-Hydroxy-50-chlorobenzyl)imidazolidines 1 and
Scheme 1.

2484
Rivera et al.
Scheme 2.
N,N0-bis(2-hydroxy-5-chlorobenzyl)ethylenediamines 2 form complexes and
can be theoretically directly used as tetradented ligands or serve as base
materials for synthesizing new ligands.[11] As an example of their use as
base materials in synthesizing new ligands, a new family of 2-substituted-1,
3-bis(20-hydroxy-50-substituted-benzyl)imidazolidine 3a–f tetrahydrosalens
was synthesized by the reaction of 2 with some aldehydes or ketones
(Sch. 2) which also form complexes whose structure is being currently studied
by our research group. This represents a new, convenient asymmetrical tetra-
hydrosalen synthetic route having good yield (Table 2) for simple reactions
and can be done using commercially available reagents.
In conclusion, our protocol provides an expedient approach to unsub-
stituted tetrahydrosalens and substituted tetrahydrosalens derived from a variety
of phenols and aromatic aldehydes or aliphatic ketones. The main advantages of
this method over previous ones are the ready availability of reagents, high yields
for various carbonyl compounds, and operational simplicity.
ACKNOWLEDGMENTS
´
The authors gratefully acknowledge Departamento de Quımica of
´
the Universidad Nacional de Colombia and the Fundacion Instituto de
Inmunologia de Colombia.
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Tetrahydrosalen Synthesis from Mannich-Type Bases
2485
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Received in the USA March 2, 2004