A convenient "one-pot" reaction for selective monoalkylation of N,N′-disubstituted ethylenediamines

Article abstract of DOI:10.1081/SCC-120023441

A study on the scope of the method to obtain N,N,N′-trisubstituted ethylenediamines III by monoalkylation of N,N′-disubstituted ethylenediamines I through a "one-pot" reaction is presented. It involves condensation of compounds I with aldehydes followed by reduction of the formed imidazolidines II without previous isolation.

Full text of DOI:10.1081/SCC-120023441

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A Convenient “One-Pot” Reaction for Selective
Monoalkylation of N,N′-Disubstituted Ethylenediamines
Alejandra Salerno a , María Amalia Figueroa a & Isabel A. Perillo a
a Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín, Buenos Aires,
Argentina
Published online: 17 Aug 2006.
To cite this article: Alejandra Salerno , Mara Amalia Figueroa & Isabel A. Perillo (2003) A Convenient “One-Pot” Reaction for
Selective Monoalkylation of N,N′-Disubstituted Ethylenediamines, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 33:18, 3193-3204, DOI: 10.1081/SCC-120023441
To link to this article: http://dx.doi.org/10.1081/SCC-120023441
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 18, pp. 3193–3204, 2003
A Convenient ‘‘One-Pot’’ Reaction for
Selective Monoalkylation of
N,N0-Disubstituted Ethylenediamines
Alejandra Salerno, Marıa Amalia Figueroa,
*
and Isabel A. Perillo
Facultad de Farmacia y Bioquımica,
Universidad de Buenos Aires, Junın,
Buenos Aires, Argentina
ABSTRACT
A study on the scope of the method to obtain N,N,N0-trisubstituted
ethylenediamines III by monoalkylation of N,N0-disubstituted ethy-
lenediamines I through a ‘‘one-pot’’ reaction is presented. It involves
condensation of compounds I with aldehydes followed by reduction
of the formed imidazolidines II without previous isolation.
Key Words: Disubstituted ethylenediamines; Selective monoalkyla-
tion; Imidazolidines; Microwaves.
*Correspondence: Isabel A. Perillo, Facultad de Farmacia
y Bioquımica,
Universidad de Buenos Aires, Junın, 956 (1113) Buenos Aires, Argentina;
Fax: 54-11-4508-3645; E-mail: iperillo@ffyb.uba.ar.
3193
DOI: 10.1081/SCC-120023441
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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3194
Salerno, Figueroa, and Perillo
INTRODUCTION
N,N0-Disubstituted ethylenediamines were studied either due to their
intrinsic biological activity or because they are precursors of pharmaco-
logically active compounds.[1] Especially, the interest in the synthesis of
N,N0-dibenzylethylenediamine and its analogues, homologues, and
derivatives lies in their ability to inhibit cholesterol biosynthesis.[2] In
connection with this, improvement of the synthesis of N,N0-dibenzyl-
ethylenediamines has been a matter of special concern.[3]
On the other hand, N,N,N0-trisubstituted ethylenediamines are
important in organic synthesis and pharmaceutical research[4] as hypo-
tensive[5] and chemoterapeutic agents[6] and as precursors of analgesic
compounds.[7]
In general, attainment of such selectively N-substituted diamine deri-
vatives by direct alkylation does not give satisfying results. Improvement
of the classic selective alkylation methods as well as development of new
synthetic strategies is always pursued.[8] Related to this, selective alkyla-
tion of diamines through the synthesis and subsequent reduction of cyclic
aminals has been reported.[9] Taking into account that imidazolidine
synthesis by condensation of N,N0-disubstituted ethylenediamines with
aldehydes,[10] as well as their reduction[11] are easy steps, a combination
of both processes could result in a promising method for N-alkylation of
properly substituted ethylenediamines.
In this work, the synthesis of a series of N,N,N0-trisubstituted
ethylenediamines III by selective monoalkylation of N,N0-disubstituted
diamines I in a ‘‘one-pot’’ reaction, involving condensation with
aldehydes and reduction of the intermediate imidazolidines II without
previous isolation, is presented (Sch. 1, Table 1).
Improvement of the synthesis of precursor N,N0-disubstituted
ethylenediamines having benzyl substituents on one or both nitrogen
atoms by means of a classical method optimized employing microwave
irradiation is reported.
R1
N
N
R2
BH4Na
R3CHO
H
R3
R1-NH-CH2-CH2-NH-R2
R1-NH-CH2-CH2-N-R2
II (8-26)
I (1-7)
CH2R3
III (27 -37)
Scheme 1.

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N,N 0-Disubstituted Ethylenediamines
Table 1. N-Substituted ethylenediamines and imidazolidines.
3195
I
II
III
R1
R2
R3
1
2
3
4
5
6
7
p-CH3OC6H4CH2
C6H5CH2
p-CH3OC6H4CH2
C6H5CH2
p-ClC6H4CH2
p-ClC6H4
p-NO2C6H4
p-ClC6H4CH2
C6H5CH2
C6H5CH2
p-CH3C6H4
CH3
CH3
p-CH3OC6H4
p-CH3OC6H4CH2
p-CH3OC6H4CH2
p-CH3OC6H4CH2
p-CH3OC6H4CH2
p-CH3OC6H4CH2
p-CH3OC6H4CH2
C6H5CH2
8
9
27
28
29
p-CH3OC6H4CH2
p-CH3OC6H4CH2
p-CH3OC6H4CH2
p-CH3OC6H4CH2
p-CH3OC6H4CH2
p-CH3OC6H4CH2
C6H5CH2
H
CH3
C6H5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
m-NO2C6H4
m-ClC6H4
CH¼CHC6H5
p-CH3OC6H4
C6H5
30
31
32
p-ClC6H4CH2
p-ClC6H4CH2
p-ClC6H4
p-ClC6H4CH2
p-ClC6H4CH2
C6H5CH2
m-ClC6H4
H
CH3
33
34
35
p-ClC6H4
p-ClC6H4
C6H5CH2
C6H5CH2
C6H5
p-NO2C6H4
p-NO2C6H4
C6H5CH2
C6H5CH2
H
CH3
p-NO2C6H4
p-NO2C6H4
C6H5CH2
C6H5CH2
C6H5
o-ClC6H4
p-CH3OC6H4
C6H5
p-NO2C6H4
p-CH3C6H4
p-CH3OC6H4
C6H5CH2
CH3
CH3
36
37
C6H5
RESULTS AND DISCUSSION
N,N0-Disubstituted ethylenediamines carrying benzyl substituents on
one or both nitrogen atoms (compounds 1–5) (Table 1) were synthesized
by condensation of ethylenediamine or N-arylethylenediamines with aro-
matic aldehydes and further reduction of the obtained Schiff bases (IV,V)
with sodium borohydride (Sch. 2).
The condensation was carried out employing a microwave-assisted
solventfree reaction [12,13], resulting in short reaction times, excellent yield
and highly pure products (Table 2).
N,N0-Disubstituted ethylenediamines 1–7 were converted in the cor-
responding trisubstituted diamines 27–37 through their transformation

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Salerno, Figueroa, and Perillo
2 Ar-CHO
Ar-HC=N-CH2-CH2-N=CH-Ar
NH2-CH2-CH2-NH2
IV
BH4Na
Ar=C6H5, p-CH3OC6H4,
p-ClC6H4
R1-NH-CH2-CH2-NH-R2
(1-5)
I
BH4Na
Ar-CHO
R1-NH-CH2-CH2-N=CH-Ar
R1-NH-CH2-CH2-NH2
V
R1=p-ClC6H4, p-NO2C6H4
Ar=C6H5
Scheme 2.
Table 2. Microwave induced condensation of ethylenediamines with aldehydes.
Molar ratio
ethylenediamine/ Time Power Yield
Compound
aldehyde
(min) (W)
(%)
[14]
IV, Ar ¼ C6H5
1:2
1:2
1:2
1:1
1:1
3
3
5
7
6
300
400
400
600
500
98
94
96
95
93
[10d]
IV, Ar ¼ p-CH3OC6H4
[15]
IV, Ar ¼ p-ClC6H4
[16]
V, R1 ¼ p-ClC6H4, Ar ¼ C6H5
[17,18]
V, R1 ¼ p-NO2C6H4, Ar ¼ C6H5
into imidazolidines II and in situ reduction employing sodium boro-
hydride. For this purpose, compounds I in ethanol were treated with
the aldehyde in the appropriate molar ratio at reflux. Reactions were
monitored by TLC until starting material disappeared and only imida-
zolidine II was observed as product. At this point, an excess of sodium
borohydride was added in small portions until transformation in the
corresponding N,N,N0-trisubstituted ethylenediamine III was complete.
Following this procedure, reaction of diamines 1–3 with formalde-
hyde, acetaldehyde, benzaldehyde, p-methoxybenzaldehyde, and cinna-
maldehyde, and further reduction, led to N,N,N0-trisubstituted
ethylenediamines III (27–32) as final products. Similarly, diamines 4, 6,
and 7 were regioselectively substituted on the alkyl (or aralkyl) nitrogen
affording compounds 33–37. Reduction of aminals II under the same
conditions usually failed when the aryl group on nitrogen or C2 had

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N,N 0-Disubstituted Ethylenediamines
3197
electron withdrawing substituents. Thus, imidazolidines 11,12,16 and
20–24 were the final reaction products.
The structural assignments of new compounds were based on
microanalyses and spectroscopic properties (Table 3).
Regioselectivity of imidazolidine reductive cleavage is mainly deter-
mined by the nature of substituents on nitrogen and C2. Reaction evolves
through an intermediate carbocation-iminium ion, and its formation
depends on the electron disponibility on such atoms.[11c] Thus, N-aryl-
N0-alkyl substituted aminals 17–19, 25 and 26 are cleaved atthe ArN-C
2
bond, due to the greater electron lone pair disponibility of aliphatic
nitrogen for the intermediate ion stabilization.
The low electron disponibility in compounds with a C2-aryl group
with electron withdrawing substituents (Cl, NO2, compounds 11, 12, and
16) or when the nitrogen atom is substituted with a strong electron with-
drawing group ( p-nitrophenyl, compounds 20–24)[19] explains the failure
of the cleavage in these derivatives independently of the nature of the
other groups, thus representing a limitation for this synthetic method.[20]
EXPERIMENTAL
Melting points were determined with a Buchi capillary apparatus and
are uncorrected. NMR spectra were recorded on a Bruker MSL 300 MHz
spectrometer using deuteriochloroform as the solvent. Chemical shifts are
reported in ppm relative to TMS as an internal standard. D2O was
employed to confirm exchangeable protons. Splitting multiplicities are
reported as singlet (s), broad signal (bs), doublet (d), triplet (t), quartet
(q), and multiplet (m). Mass spectra (EI) were recorded with a GC-MS
Shimadzu QP-1000 spectrometer operating at 20 eV. TLC analyses
were carried outon aluminium sheest silica gel 60 F
using benzene–
254
methanol (9:1) as the solvent. Column chromatographies were performed
on silica gel 60 (230–400 mesh) with typically 30–50 g of stationary phase
per gram substance employing the same eluent. Microwave reactions
were carried outin a domestic microwave oven.
Synthesis of N,N0-Disubstituted Ethylenediamines (I)
N-Aryl-N0-methylethylenediamines 6[21] and 7[22] were synthesized
from N-(2-bromoethyl)methylamine hydrobromide and the correspond-
ing arylamines following literature procedures.

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N,N 0-Disubstituted Ethylenediamines
3199

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Compound 1–5 were synthesized from ethylenediamines and
aldehydes employing the following method.
General Procedure
A mixture of ethylenediamine or N-arylethylenediamine and the
appropriate benzaldehyde in an open Erlenmeyer flask was heated in a
domestic microwave oven until total consumption of the starting material
(TLC). Dilution of the reaction mixture with water usually led to the
precipitation of compounds IV or V, which were filtered and washed
abundantly with water. Molar ratios, reaction times, literature data
and yields are given in Table 2.
To a solution of compounds IV and V (0.01 mol) in ethanol (20 mL)
sodium borohydride (0.05 mol) was added. The reaction mixture was
heated under reflux for ca. 3 h. Water (20 mL) was added and the solution
was extracted with chloroform (3 ꢀ 20 mL). The combined organic layers
were washed with water, dried and concentrated. Compounds 1,[10d] 2,[14]
3,[23] 4,[8a] and 5[8a] were purified by column chromatography and their
1
structures confirmed by H-NMR and mass spectrometry.
MONOALKYLATION OF ETHYLENEDIAMINES I:
‘‘ONE-POT’’ REACTION
General Procedure
A mixture of N,N0-disubstituted ethylenediamine 1–7 (0.01 mol) and
the corresponding aldehyde (0.01 mol) in ethanol (20 mL) was refluxed
and the reaction monitored by TLC. When the reactants were consumed
(ca. 2 h), sodium borohydride (0.05 mol) was added in portions. After 2 h,
water (10 mL) was added and the mixture was filtered. The aqueous
solution was extracted with chloroform (3 ꢀ 15 mL) and the combined
organic layers were washed with water, dried and concentrated.
N,N,N0-Trisubstituted ethylenediamines 27–37 were obtained in
1
60–95% yield. Elemental analyses, H-NMR and MS data are given in
Table 3.
Imidazolidines 11,[10d] 12, 16, and 20–24 remained unaltered in the
reductive media and were isolated as the final reaction products.
1,3-Di( p-methoxybenzyl)-2-(m-nitrophenyl)imidazolidine (11). M.p.:
154–155ꢁC, m.p. (Lit.): 154ꢁC.[10d] 1H NMR: ꢀ ¼ 2.55 (m, 2H), 3.15

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N,N 0-Disubstituted Ethylenediamines
3201
(m, 2H), 3.30 (d, 2H), 3.65 (d, 2H), 3.73 (s, 6H), 3.95 (s, 1H), 6.75 (d, 4H),
7.10 (d, 4H), 7.50 (t, 1H), 7.90 (d, 1H), 8.17 (d, 1H), and 8.90 (s, 1H).
2-(m-Chlorophenyl)-1,3-di( p-methoxybenzyl)imidazolidine (12). M.p.:
122ꢁC (Ethanol). MS: m/z 422 (Mþ.). H NMR: ꢀ ¼ 2.50 (m, 2H), 3.10
1
(m, 2H), 3.25 (d, 2H), 3.61 (d, 2H), 3.70 (s, 6H), 3.87 (s, 1H), 6.80 (d, 4H),
7.15 (d, 4H), 7.20 (m, 3H), and 7.60 (s, 1H). Anal. calcd. for
C25H27N2ClO2: C 70.99, H 6.43, N 6.62. Found: C 71.08 , H 6.35, N 6.51.
1,3-Di( p-chlorobenzyl)-2-(m-chlorophenyl)imidazolidine (16). M.p.:
81–83ꢁC (Ethanol). MS: m/z 430 (Mþ.). 1H NMR: ꢀ ¼ 2.47 (m, 2H),
3.05 (m, 2H), 3.15 (d, 2H), 3.65 (d, 2H), 3.80 (s, 1H), 7.00–7.30 (m,
10H), 7.45 (m, 1H), and 7.60 (s, 1H). Anal. calcd. for C23H21N2Cl3: C
63.98 , H 4.90, N 6.49. Found: C 64.10 , H 4.80, N 6.61.
1-Benzyl-3-( p-nitrophenyl)imidazolidine (20). Itwas obatined as
an oil.[24]
1-Benzyl-2-methyl-3-(p-nitrophenyl)imidazolidine (21). Itwas obtained
1
as an oil. MS: m/z 297 (Mþ.). H-NMR: ꢀ ¼ 1.40 (d, 3H), 2.90 (m, 1H),
3.61 (d, 1H), 3.70 (m, 2H), 3.71 (d, 1H), 3.90 (c, 1H), 4.01 (d, 1H), 6.49 (d,
2H), 7.35 (m, 5H) and 8.10 (d, 2H). Anal. calcd. for C17H19N3O2: C 68.67
, H 6.44 , N 14.13. Found: C 68.70, H 6.36, N 14.25.
1-Benzyl-2-phenyl-3-( p-nitrophenyl)imidazolidine (22). MS: m/z 359
(Mþ.). M.p.: 120–122ꢁC (Ethanol). H NMR: ꢀ ¼ 2.90 (m, 1H), 3.20 (m,
1
1H), 3.51 (d, 1H), 3.63–3.71 (m, 3H), 5.20 (s, 1H), 6.45 (d, 2H), 7.27(m,
10H) and 8.01 (d, 2H). Anal. calcd. for C22H21N3O2: C 73.52, H 5.89, N
11.69. Found: C 73.65, H 5.82, N 11.78.
1-Benzyl-2-(o-chlorophenyl)-3-( p-nitrophenyl)imidazolidine (23). MS:
m/z 393 (Mþ.). M.p.: 125–127ꢁC (Ethanol). H NMR: ꢀ ¼ 2.95 (m, 1H),
1
3.20 (m, 1H), 3.61 (d, 1H), 3.71 (m, 2H), 3.97 (d, 1H), 5.70 (s, 1H), 6.40
(d, 2H), 7.30 (m, 7H), 7.45 (d, 2H) and 8.10 (d, 2H). Anal. calcd. for
C22H20N3ClO2: C 67.09, H 5.12, N 10.67. Found: C 67.20 , H 5.06,
N 10.83.
1-Benzyl-2-( p-methoxyphenyl)-3-( p-nitrophenyl)imidazolidine
(24).
MS: m/z 389 (Mþ.). M.p.: 124–125ꢁC (Ethanol). H NMR: ꢀ ¼ 2.90 (m,
1H), 3.20 (m, 1H), 3.50 (d, 1H), 3.60–3.70 (m, 3H), 3.80 (s, 3H), 5.10 (s,
1H), 6.40 (d, 2H), 6.81 (d, 2H), 7.15 (d, 2H), 7.20–7.35 (m, 5H), and 8.00
(d, 2H). Anal. calcd. for C23H23N3O3: C 70.93, H 5.95, N 10.79. Found:
C 70.77, H 6.02, N 10.87.
1
ACKNOWLEDGMENT
This work was financially supported by the Universidad de Buenos
Aires and CONICET.

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1
The H-NMR spectrum in deuteriochloroform shows characteristic
signals a ꢀ ¼ 5.50 ppm (s, imidazolidine C2-H) and ꢀ ¼ 8.37 ppm (s,
N ¼ CH-Ar) (imine:imidazolidine, 35:65). Anal. calcd. for
C15H15ClN2: C 69.63, H 5.84, N 10.83; Found: C 69.52, H 5.76,
N 10.70.
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Received in the USA December 18, 2002