Synthesis of a new series of N,N'-dimethyltetrahydrosalen (H2 [H2Me]salen) ligands by the reductive ring-opening of 3,3'-ethylene-bis(3,4-dihydro-6-substituted-2H-1,3-benzoxazines)

Article abstract of DOI:10.3390/molecules15064102

A new series of N, N'-bis(2'-hydroxy-5'-substituted-benzyl)-N, N'-dimethylethane-1,2-diamines (N, N'-dimethyltetrahydrosalen) ligands were prepared in good yield by reduction of the respective 3,3'-ethylene-bis(3,4- dihydro-6-substituted-2H-1,3-benzoxazine) precursors with sodium borohydride. The ligands were characterized by IR, NMR, and elemental analysis, which showed the compounds to be consistent with the proposed structures. Ring-opening reactions of bis-1,3-benzoxazines in the presence of sodium borohydride to produce N, N'-dimethylated tetrahydrosalens (H₂ [H ₂Me]salen) have not been reported in the literature.

Full text of DOI:10.3390/molecules15064102

Molecules 2010, 15, 4102-4110; doi:10.3390/molecules15064102
OPEN ACCESS
molecules
www.mdpi.com/journal/molecules
ISSN 1420-3049
Article
Synthesis of a New Series of N,N’-Dimethyltetrahydrosalen (H2
[H2Me]salen) Ligands by the Reductive Ring-Opening of 3,3'-
Ethylene-bis(3,4-dihydro-6-substituted-2H-1,3-benzoxazines)
Augusto Rivera *, Jicli José Rojas, Jairo Salazar-Barrios, Mauricio Maldonado and
Jaime Ríos-Motta
Departamento de Química, Universidad Nacional de Colombia, Bogotá, Colombia, A.A. 14490, Colombia
* Author to whom correspondence should be addressed; E-Mail: ariverau@unal.edu.co;
Tel.: +571-3165000; Fax: +571-3165220.
Received: 26 April 2010; in revised form: 7 May 2010 / Accepted: 11 May 2010 /
Published: 7 June 2010
Abstract:
A
new
series
of
N,N'-bis(2'-hydroxy-5'-substituted-benzyl)-N,N´-
dimethylethane-1,2-diamines (N,N'-dimethyltetrahydrosalen) ligands were prepared in
good yield by reduction of the respective 3,3'-ethylene-bis(3,4-dihydro-6-substituted-2H-
1,3-benzoxazine) precursors with sodium borohydride . The ligands were characterized by
IR, NMR, and elemental analysis, which showed the compounds to be consistent with the
proposed structures. Ring-opening reactions of bis-1,3-benzoxazines in the presence of
sodium borohydride to produce N,N’-dimethylated tetrahydrosalens (H2 [H2Me]salen) have
not been reported in the literature.
Keywords: tetrahydrosalen; salan; bis-benzoxazines; tetradentate ligand
1. Introduction
The salen-type class of ligands (H2 salen; N,N’-disalicylidene-1,2-diaminoethane; 1, Figure 1) has
had an extensive and continuing history in transition metal chemistry. Hydrogenation of the imine
bond of salen compounds produces a new tetradentate ligand, which is known generally as salan
(H2[H4]salen; tetrahydrosalen; N,N’-bis(2-hydroxybenzyl)-1,2-diaminoethane; 2, Figure 1) [1]. While
the salen ligands feature two sites capable of covalent bonding with an electropositive element, the H4
salan ligands contain four such sites, and are therefore ideally suited to bind multiple metals [2].

Molecules 2010, 15
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Figure 1. Structures of compounds 1-3.
OH
N
OH
OH
H
N
N
H
N
N
N
HO
HO
HO
1
2
3
Tetrahydrosalen-type ligands are intimately involved with a number of metal coordination
complexes, which include those elements located in groups 12, 13 and 14 [3]. Some of them have been
mostly studied in polymerization catalysis in the past ten years [4-6]. Interest in these tetradentate
ligands, whose properties may be manipulated by changing the bridging unit between the two nitrogen
atoms, the substituents on the amine group, or the substitution patterns on the phenols, has stimulated
research efforts in developing synthetic procedures to obtain a variety of these compounds [7-15].
Tetrahydrosalen, N,N’-dimethylated tetrahydrosalen 3 and its derivatives have rarely been studied, and
the most common approach for the preparation of this class of compounds has involved the isolation of
the salan intermediate followed by additional substitution steps on the salan products [16,17], or
condensation of salans with formaldehyde/acetic acid followed by in situ sodium borohydride
reduction to give the N-methylated salans [18]. Other procedures employ the reductive amination of
N,N'-dimethylethylene diamine with NaBH3(CN) [19,20]. Recently, Tshuva et al. [14] reported a
single-step synthetic procedure enabling the preparation in high yield of a variety of salan compounds,
including N,N-disubstituted salans, by a Mannich condensation of substituted phenols, formaldehyde
and N,N’-substituted-diamines. In a series of earlier works, we reported on the successful synthesis of
3,3'-ethylene-bis(3,4-dihydro-6-substituted-2H-1,3-benzoxazines) (BISBOAs) thru the condensation of
p-substituted phenols, formaldehyde and ethylenediamine [21-23]. Herein, we report on the usefulness
of these compounds for the expedient synthesis of a new series of N,N’-dimethylated tetrahydrosalens.
Based on a comparison of the basicity of tetrahydrosalen and salen, where the basicity decreases,
we expected that the methyl functionality in tetrahydrosalens would provide the best template for
metal binding. On the other hand, it is well known that tetrahydrosalen associated with metal centers
displays cis-octahedral coordination geometry, which can form two possible diastereomers (cis fac-
mer and cis fac-fac) [24]. Each of these can exist as a pair of chiral-at-metal enantiomers [8].
2. Results and Discussion
The overall procedure for the preparation of N,N'-bis(2'-hydroxy-5'-substituted-benzyl)-N,N´-
dimethylethane-1,2-diamines 6a-h is depicted in Scheme 1. The 3,3'-ethylene-bis(3,4-dihydro-6-
substituted-2H-1,3-benzoxazines) 5a-h used were prepared according to a previously reported
procedure [21-23] that involves a one-pot condensation–cyclization reaction of the appropriate phenol
4a-h with an excess of 37% aqueous formaldehyde and ethylenediamine in a mixture of dioxane
and water.

Molecules 2010, 15
Scheme 1. Synthesis of the N,N´-dimethylsalan from the BISBOAs.
4104
OH
O
H2N
N
R
+ H2C=O +
NH2
R
N
O
R
4a-h
5a-h
NaBH4
OH
N
R
R
N
HO
6a-h
Based on previous results reported for the reduction of naphtho-1,3-oxazines [25] and
benzo-1,3-oxazines we anticipated that the reaction between compounds 5a-h and sodium borohydride
would yield tetrahydrosalens 6a-h [26]. Additionally, the efficacy of sodium borohydride as a reducing
agent should give the expected tetrahydrosalen products. In fact, the reduction with sodium
borohydride of the appropriate BISBOAs (5a-h) to the respective N,N'-dimethylated tetrahydrosalens
occurs readily and with good yields, ranging from 36% to 70% (Table 1). The structures of all the
1
synthesized molecules were confirmed by elemental analysis and spectral (FT-IR, H-NMR,
13C-NMR) data. The FT-IR spectra of compounds 6a-h lack the characteristic absorption peaks of the
O-CH2-N methylene group of the benzoxazine ring structure at 1,226 cm-1 (asymmetric stretching of
C–O–C) and 1,035 cm-1 (symmetric stretching of C–O–C). The spectra did show, however, the
presence of a OH group with absorptions near 3,400 cm-1. In the 1H-NMR, characteristic peaks of the
1,3-oxazine ring were not observed at ca. 5.0 ppm, but a new two-methyl singlet (6H) appeared with a
chemical shift range of 2.21–2.30 ppm. This indicates that the double reduction of 5a-h with NaBH4
proceeds by the chemoselective cleavage of the O-CH2 bond of the N,O-acetal moiety of BISBOAs.
This chemoselectivity may be related to the preference of the boron atom toward alkoxy complex
formation, which is more favorable to a subsequent hydrolysis reaction than the aminoborane obtained
by reductive cleavage of the CH2-N bond. A reduction mechanism in two steps is proposed in Scheme 2.

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Table 1. Substrate scope of reduction of BISBOAs.
Entry
Compound
R
F
Product
6a
Yield (%)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
38
61
40
59
36
66
70
68
Cl
6b
Br
6c
I
6d
COOMe
COOEt
COOPr
COOBu
6e
6f
5g
5h
6g
6h
Scheme 2. Mechanism of reduction of 5a-h with NaBH4.
H
B
H
H
B
O
H
H
H
H
O
N
R
N
R
R
N
R
N
H
O
O
B
H
H
B
H
H
H
H
CH3OH
OH
N
R
+ B(OCH3)4
R
N
HO
3. Experimental
3.1. General
The 3,3'-ethylene-bis(3,4-dihydro-6-substituted-2H-1,3-benzoxazines) 5a-h used were prepared
according to the literature procedure [21-23]. Chemicals were used without further purification, and
1
infrared spectra were recorded on a Perkin–Elmer FT-IR Paragon spectrometer with a KBr disk. H-
and 13C-NMR spectra were measured on a Bruker Advance 400 MHz spectrometer in CDCl3 operating
at 400 MHz and 100 MHz, respectively. Elemental analyses (C, H, N) were determined in a Carlo-
Erba model 1106 analyzer. Melting points (uncorrected) were determined on an Electrothermal 9100
melting point apparatus.
3.2. General procedure for synthesis of BISBOAs
To a stirred and cooled solution of formaldehyde 37% (2.8 mL, 37.4 mmol) in dioxane (40 mL) is
added slowly dropwise ethylenediamine (0.65 mL, 9.36 mmol). After stirring for 15 min at 5 ºC a
solution of respectively 4-substituted-phenol (18.7 mmol) in dioxane (17 mL) is added dropwise with

Molecules 2010, 15
4106
stirring. The mixture is gently refluxed for 4–24 h. After cooling to room temperature, the solvent is
removed in vacuo and the crude product is recrystallized from methanol.
3,3'-ethylene-bis(3,4-dihydro-6-chloro-2H-1,3-benzoxazine) (5b). m.p. 170.2 ºC (literature [22]:
1
170–173 ºC). H-NMR δ (ppm): 3.02 (s, 4H, NCH2CH2N), 3.99 (s, 4H, Ar-CH2-N), 4.87 (s, 4H, O-
CH2-N), 6.75 (d, 2H, J = 8.66 Hz, Ar-H), 6.94 (d, 2H, J = 2.4 Hz, Ar-H), 7.10 (dd, 2H, J = 8.66 Hz,
13
J = 2.4 Hz, Ar-H). C-NMR δ (ppm): 49.6, 50.3, 82.8, 117.9, 121.4, 125.3, 127.2, 127.8, 152.7. The
spectral data were consistent with literature values [22].
3,3'-ethylene-bis(3,4-dihydro-6-bromo-2H-1,3-benzoxazine) (5c). m.p. 177.2 ºC (literature [23]:
1
178–179 ºC). H-NMR δ (ppm): 2.91 (s, 4H, NCH2CH2N), 3.98 (s, 4H, Ar-CH2-N), 4.85 (s, 4H, O-
CH2-N), 6.65 (d, 2H, J = 8.66 Hz, Ar-H), 7.06 (d, 2H, J = 2.4 Hz, Ar-H), 7.19 (dd, 2H, J = 8.66 Hz,
13
J = 2,4 Hz, Ar-H). C-NMR δ (ppm): 49.4, 51.2, 82.1, 110.6, 117.7, 121.0, 129.9, 131.4, 153.6. The
spectral data were consistent with literature values [23].
Dimethyl 3,3'-(ethane-1,2-diyl)bis(3,4-dihydro-2H-benzo[e][1,3]oxazine-6-carboxylate) (5e). m.p.
152.2 ºC (literature [22]: 151–154 ºC). 1H-NMR δ (ppm): 2.96 (s, 4H, NCH2CH2N), 3.89 (s, 6H, CH3-
O), 4.06 (s, 4H, Ar-CH2-N), 4.97 (s, 4H, O-CH2-N), 6.77 (d, 2H, J = 8.4 Hz, Ar-H), 7.69 (d, 2H,
13
J = 2.0 Hz, Ar-H), 7.83 (dd, 2H, J = 8.4 Hz, J = 2.0 Hz, Ar-H). C-NMR δ (ppm): 49.6, 50.2, 51.8,
83.3, 116.4, 119.4, 122.8, 129.6, 129.7, 158.2, 162.2. The spectral data were consistent with literature
values [22].
Diethyl 3,3'-(ethane-1,2-diyl)bis(3,4-dihydro-2H-benzo[e][1,3]oxazine-6-carboxylate) (5f). m.p.
142.5 ºC. 1H-NMR δ (ppm): 1.38 (t, J = 8.00 Hz, 6H, CH3-CH2-O), 2.95 (s, 4H, NCH2CH2N), 4.07 (s,
4H, Ar-CH2-N), 4.24 (q, J = 8.00 Hz, 4H, CH3-CH2-O), 4.97 (s, 4H, O-CH2-N), 6.78 (d, 2H,
13
J = 8.4 Hz, Ar-H), 7.69 (d, 2H, J = 2.0 Hz, Ar-H), 7.81 (dd, 2H, J = 8.4 Hz, J = 2.0 Hz, Ar-H). C-
NMR δ (ppm): 13.6, 49.6, 50.3, 51.8, 83.3, 116.4, 119.4, 122.8, 129.6, 129.7, 158.2, 162.2.
Dipropyl 3,3'-(ethane-1,2-diyl)bis(3,4-dihydro-2H-benzo[e][1,3]oxazine-6-carboxylate) (5g). m.p.
1
127.2–127.9 ºC. H-NMR δ (ppm): 1.02 (t, J = 7.5 Hz, 6H, CH3-CH2-O), 1.79 (m, J = 7.5 Hz, 4H,
CH3-CH2-CH2-O), 2.95 (s, 4H, NCH2CH2N), 4.07 (s, 4H, Ar-CH2-N), 4.22 (t,
J = 7.6 Hz, 4H, CH3-CH2-CH2-O), 4.95 (s, 4H, O-CH2-N), 6.78 (d, 2H, J = 8.4 Hz, Ar-H), 7.69 (d,
13
2H, J = 2.0 Hz, Ar-H), 7.81 (dd, 2H, J = 8.4 Hz, J = 2.0 Hz, Ar-H). C-NMR δ (ppm): 10.5, 22.2,
49.6, 50.3, 53.8, 83.3, 116.4, 119.4, 122.8, 129.6, 129.7, 158.2, 162.2.
Dibutyl 3,3'-(ethane-1,2-diyl)bis(3,4-dihydro-2H-benzo[e][1,3]oxazine-6-carboxylate) (5h). m.p.
89.2 ºC. 1H-NMR δ (ppm): 0.95 (t, J = 7.40 Hz, 6H, CH3-CH2-CH2-CH2-O), 1.49 (m, 4H, CH3-CH2-
CH2-CH2-O), 1.72 (q, J = 6.63 Hz, 4H, CH3-CH2-CH2-CH2-O), 2.93 (s, 4H, NCH2CH2N), 4.07 (s, 4H,
Ar-CH2-N), 4.32 (t, J = 6.61 Hz, 4H, CH3-CH2-CH2-CH2-O), 4.95 (s, 4H, O-CH2-N), 6.78 (d, 2H,
13
J = 8.3 Hz, Ar-H), 7.68 (d, 2H, J = 2.0 Hz, Ar-H), 7.80 (dd, 2H, J = 8.3 Hz, J = 2.0 Hz, Ar-H). C-
NMR δ (ppm): 13.8, 19.3, 30.9, 49.7, 50.3, 51.8, 83.4, 116.4, 119.5, 122.8, 129.6, 129.7, 158.2, 162.2.

Molecules 2010, 15
4107
3.3. General procedure for reduction of BISBOAs
Sodium borohydride (3.0 mmol, 0.11 g) was added to a solution of the appropriate benzoxazine
(1 mmol) in ethanol (15 mL), and the mixture was stirred magnetically for 30 min at room
temperature. The progress of the reaction was monitored by thin-layer chromatography (TLC). After
completion of the reaction, the mixture was poured into ice-cold water, neutralized with ammonium
chloride (12 mL), and extracted with CHCl3 (3 × 10 cm3). The combined extracts were dried over
anhydrous Na2SO4 and evaporated. The solid obtained was purified by recrystallization from ethanol to
the desired products 6a-h.
N,N´-bis(2-hydroxy-5-fluorobenzyl)-N,N´-dimethylethane-1,2-diamine (6a). White solid, yield 38%,
m.p. 110–112 ºC. IR: 3432 cm-1 (O-H), 2849 cm-1 (N-CH3 str.) 1H-NMR δ (ppm): 2.28 (s, 6H, H3C-N),
2.65 (s, 4H, NCH2CH2N), 3.65 (s, 4H, Ar-CH2-N), 6.65 (dd, 2H, J = 2.0 Hz, J = 24.4 Hz, Ar-H), 6.76
(dd, 2H, J = 8.7 Hz, J = 4.7 Hz, Ar-H), 6.86 (dd, 2H, J = 8.4 Hz, J = 2.4 Hz, J = 16.8 Hz). 13C-NMR
δ (ppm): 41.7, 53.9, 61.4, 114.9, 115.2, 116.9, 122.4, 153.6, 156.0. Elem. anal. calcd. for
C18H22F2N2O2: C 70.58%, H 6.59%, N 8.33%; found C 70.39%, H 6.54%, N 8.39%.
N,N´-bis(2-hydroxy-5-chlorobenzyl)-N,N´-dimethylethane-1,2-diamine (6b). White solid, yield 61%,
m.p. 172–174 ºC. IR: 3434 cm-1 (O-H), 2849 cm-1 (N-CH3 str.). 1H-NMR [400 MHz, δ (ppm), CDCl3]:
2.21 (s, 6H, H3C-N), 2.58 (s, 4H, NCH2CH2N), 3.59 (s, 4H, Ar-CH2-N), 6.70 (d, 2H, J = 8.8 Hz, Ar-
H), 6.87 (d, 2H, J = 2.4 Hz, Ar-H), 7.05 (dd, 2H, J = 8.8 Hz, J = 2.4 Hz, Ar-H). 13C-NMR [100 MHz,
δ (ppm), CDCl3]: 40.6, 52.8, 60.2, 116.5, 121.9, 122.6, 127.1, 127.7, 155.3. Elem. anal. calcd. for
C18H22Cl2N2O2: C 58.54%, H 6.00%, N 7.59%; found C 58.29%, H 5.84%, N 7.63%.
N,N´-bis(2-hydroxy-5-bromobenzyl)-N,N´-dimethylethane-1,2-diamine (6c). White solid, yield 40%,
1
m.p. 181–183 ºC. IR: 3432 cm-1 (O-H), 2850 cm-1 (N-CH3 str.). H-NMR δ (ppm): 2.23 (s, 6H, H3C-
N), 2.65 (s, 4H, NCH2CH2N), 3.58 (s, 4H, Ar-CH2-N), 6.73 (d, 2H, J = 8.8 Hz, Ar-H), 7.08 (d, 2H,
J = 2.4 Hz, Ar-H), 7.05 (dd, 2H, J = 8.8 Hz, J = 2,4 Hz, Ar-H). 13C-NMR
(ppm): 41.5, 53.7, 61.1,
110.7, 117.9, 123.3, 130.9, 131.6, 156.8. Elem. anal. calcd. for C18H22Br2N2O2: C 47.18%, H 4.84%, N
6.11%; found C 47.19%, H 4.54%, N 6.08%.
N,N´-bis(2-hydroxy-5-iodobenzyl)-N,N´-dimethylethane-1,2-diamine (6d). White solid, yield 59%,
1
m.p. 170–171 ºC. IR: 3431 cm-1 (O-H), 2849 cm-1 (N-CH3 str.). H-NMR δ (ppm): 2.27 (s, 6H, H3C-
N), 2.64 (s, 4H, NCH2CH2N), 3.64 (s, 4H, Ar-CH2-N), 6.62 (d, 2H, J = 8.4 Hz, Ar-H), 7.12 (d, 2H,
13
J = 2.0 Hz, Ar-H), 7.36 (dd, 2H, J = 8.4 Hz, J = 2,0 Hz, Ar-H). C-NMR δ (ppm): 41.5, 53.7, 60.9,
80.4, 118.5, 124.0, 136.8, 137.6, 157.6. Elem. anal. calcd. for C18H22I2N2O2: C 39.15%, H 4.02%, N
5.07%; found C 38.96%, H 3.99%, N 5.03%.
N,N´-bis(2-hydroxy-5-methoxycarbonylbenzyl)-N,N´-dimethylethane-1,2-diamine (6e). White solid,
yield 36%, m.p. 157–159 ºC. IR: 3433 cm-1 (O-H), 2848 cm-1 (N-CH3 str.), 1704 cm-1 (C=O). 1H-NMR
δ (ppm): 2.29 (s, 6H, CH3-N), 2.68 (s, 4H, NCH2CH2N), 3.75 (s, 4H, Ar-CH2-N), 3.87 (s, 6H, CH3-O),
6.85 (d, J = 8.50 Hz, 2H, Ar-H), 7.70 (d, J = 1.48 Hz, 2H, Ar-H), 7.88 (dd, J = 8.47 Hz, J= 1.94 Hz,

Molecules 2010, 15
4108
13
2H, Ar-H). C-NMR δ (ppm): 41.6, 51.8, 53.8, 61.4, 116.2, 121.0, 121.2, 130.5, 131.1, 162.4, 166.9.
Elem. anal. calcd. for C22H28N2O6: C 63.45%, H 6.78%, N 6.73%; found C 63.37%, H 6.54%, N 6.63%.
N,N´-bis(2-hydroxy-5-ethoxycarbonylbenzyl)-N,N´-dimethylethane-1,2-diamine (6f). White solid, yield
66%, m.p. 114 ºC. IR: 3449 cm-1 (O-H), 2849 cm-1 (N-CH3 str.), 1703 cm-1 (C=O). 1H-NMR δ (ppm):
1.39 (t, J = 8.00 Hz, 6H, CH3-CH2-O), 2.31 (s, 6H, CH3-N), 2.70 (s, 4H, NCH2CH2N), 3.77 (s, 4H,
Ar-CH2-N), 4.34 (q, J = 8.00 Hz, 4H, CH3-CH2-O), 6.87 (d, J = 8.00 Hz, 2H, Ar-H), 7.72 (d,
J = 2.00 Hz, 2H, Ar-H), 7.91 (dd, J = 8.00 Hz, J= 2.00 Hz, 2H, Ar-H). 13C-NMR δ (ppm): 13.6, 41.6,
53.8, 60.6, 61.5, 116.1, 121.1, 121.4, 130.4, 131.0, 162.2, 166.4. Elem. anal. calcd. for C24H32N2O6: C
64.85%, H 7.26%, N 6.30%; found C 64.72%, H 7.15%, N 6.08%.
N,N´-bis(2-hydroxy-5-propoxycarbonylbenzyl)-N,N´-dimethylethane-1,2-diamine (6g). White solid,
yield 70%, m.p. 123–125 ºC. IR: 3450 cm-1 (O-H), 2844 cm-1 (N-CH3 str.), 1700 cm-1 (C=O). 1H-NMR
δ (ppm): 1.02 (t, J = 7.42 Hz, 6H, CH3-CH2-CH2-O), 1.77 (m, J = 7.5 Hz, 4H, CH3-CH2-CH2-O), 2.29
(s, 6H, CH3-N), 2.69 (s, 4H, NCH2CH2N), 3.76 (s, 4H, Ar-CH2-N), 4.23 (t, J = 6.66 Hz, 4H, CH3-
CH2-CH2-O), 6.85 (d, J = 8.50 Hz, 2H, Ar-H), 7.71 (d, J = 1.48 Hz, 2H, Ar-H), 7.90 (dd, J = 8.49 Hz,
J = 2.02 Hz, 2H, Ar-H). 13C-NMR δ (ppm): 10.5, 22.2, 41.6, 53.8, 61.5, 66.2, 116.1, 121.0, 121.5,
130.4, 131.1, 162.3, 166.5. Elem. anal. calcd. for C26H36N2O6: C 66.08%, H 7.68%, N 5.93%; found C
65.89%, H 7.54%, N 5.78%.
N,N´-bis(2-hydroxy-5-butoxycarbonylbenzyl)-N,N´-dimethylethane-1,2-diamine (6h). White solid,
yield 68%, m.p. 117–119 ºC. IR: 3449 cm-1 (O-H), 2850 cm-1 (N-CH3 str.), 1704 cm-1 (C=O). 1H-NMR
δ (ppm): 0.97 (t, J = 7.38 Hz, 6H, CH3-CH2-CH2-CH2-O), 1.47 (m, 4H, CH3-CH2-CH2-CH2-O), 1.73
(q, J = 6.73 Hz, 4H, CH3-CH2-CH2-CH2-O), 2.30 (s, 6H, CH3-N), 2.68 (s, 4H, NCH2CH2N), 3.76 (s,
4H, Ar-CH2-N), 4.28 (t, J = 6.61 Hz, 4H, CH3-CH2-CH2-CH2-O), 6.85 (d, J = 8.50 Hz, 2H, Ar-H),
7.70 (d, J = 1.48 Hz, 2H, Ar-H), 7.89 (dd, J = 8.49, J = 2.02 Hz, 2H, Ar-H). 13C-NMR δ (ppm): 13.8,
19.3, 30.9, 41.6, 53.8, 61.5, 64.5, 116.1, 121.1, 121.5, 130.4, 131.1, 162.3, 166.5. Elem. anal. calcd. for
C28H40N2O6: C 67.18%, H 8.05%, N 5.60%; found C 67.02%, H 7.94%, N 5.43%.
4. Conclusions
In summary, we have found a novel synthetic approach for the synthesis of tetrahydrosalens. The
features of the present method include the ready availability of the starting materials, the mild reaction
conditions, and the simplicity of the workup. Because the substitution pattern on the phenols may be
varied, this simple methodology should be useful for the preparation of a variety of N,N´-dimethylated-
tetrahydrosalens. Furthermore, the simplicity of the operations involved represents a good prerequisite
for large scale applications.
Acknowledgements
We acknowledge the Dirección de Investigaciones Sede Bogotá (DIB) of Universidad Nacional de
Colombia for its financial support of this work.

Molecules 2010, 15
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References and Notes
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Sample Availability: Samples of the compounds 5a-f and 6a-f are available from the authors.
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