New synthetic routes for N-substituted 1,n-diamines. II. Synthesis of selectively N-substituted tetra- and pentamethylenediamines from ω-alkanoic acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.01.088

A new approach for the synthesis of selectively N-substituted tetra- and pentamethylenediamines 1 (n = 4,5) is described. The method uses N-substituted ω-haloalkanamides 2 as precursors and involves the microwave-promoted conversion into ω-azidocarboxamides 3 and later the reduction of both azido and carboxamide groups with diborane.

Full text of DOI:10.1016/j.tetlet.2011.01.088

Tetrahedron Letters 52 (2011) 1466–1468
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New synthetic routes for N-substituted 1,n-diamines. II. Synthesis
of selectively N-substituted tetra- and pentamethylenediamines
from
x-alkanoic acid derivatives
⇑
María A. Ramírez, María V. Corona, Gisela Ortiz, Alejandra Salerno, Isabel A. Perillo, María M. Blanco
Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 (1113), Buenos Aires, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
A new approach for the synthesis of selectively N-substituted tetra- and pentamethylenediamines 1
(n = 4,5) is described. The method uses N-substituted -haloalkanamides 2 as precursors and involves
Received 15 December 2010
Revised 7 January 2011
Accepted 18 January 2011
Available online 23 January 2011
x
the microwave-promoted conversion into
and carboxamide groups with diborane.
x-azidocarboxamides 3 and later the reduction of both azido
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
1,n-Diamines
Selectively substituted
tetra(penta)methylenediamines
Azidoamides
Microwave irradiation
Diborane reductions
N-substituted derivatives of tetra- and pentamethylenediamine
(putrescine and cadaverine, respectively) are considered analogs of
natural polyamines1 (spermine, spermidine, and putrescine). They
are interesting compounds due to the antiproliferative and cyto-
toxic activity that many of them possess.2 Dinuclear platinum
complexes of some derivatives have also been evaluated as
potential antitumor agents.3 It has also been reported that they
show fibrin-stabilizing factor (FSF) inhibitory activity,4 affinity for
muscarinic cholinergic receptors,5 affinity for NMDA receptor6,
and anti-leishmanial activity.7 The synthesis of selectively
N-substituted tetra- and pentamethylenediamines is a field of
current interest because they are synthetic precursors of poly-
amine derivatives.8
strategies, where the amine functions should be generated sequen-
tially through two different methods.9
Among others, N-monosubstituted 1,n-diamines are adequate
synthetic precursors for asymmetric N,N0-disubstituted deriva-
tives.9d Convenient synthetic routes to N-alkyl- and benzyl substi-
tuted tetra- and pentamethylenediamines have already been
described.3,10 On the other hand, we have recently described a
new method to obtain N-aryltetra- and pentamethylenediamines
1 by acid hydrolysis of the corresponding N-aryl-N0-benzoylalkyl-
enediamines using microwave irradiation.11 Other methods to
obtain such compounds have already been discussed in a previous
work reference.
In this work, we present a new approach and discuss some
alternative pathways to obtain N-monosubstituted and N,N-selec-
tively disubstituted tetra- and pentamethylenediamines 1 (n = 4,5)
(Table 1).
The synthesis of symmetrically substituted N,N0-dialkyl-(or
benzyl)tetra- and pentamethylenediamines is relatively easy. The
most common methods use the corresponding 1,n-diamine as a
precursor and imply the derivatization of the primary amino
groups by transformation in imines1,2a,b and further reduction.
These methods cannot commonly adapt to the preparation of
N,N0-asymmetrically substituted diamines since both the amino
groups in the substrate have the same reactivity. Therefore, the
preparation of these derivatives requires more complex synthetic
With the aim to search for new synthetic strategies to obtain
N-selectively substituted tetra- and pentamethylenediamines, we
considered that
x-haloalkanoic acid derivatives could be adequate
precursors to generate the tetra- or pentamethylenediamine
moiety.
⇑
Corresponding author. Tel./fax: +54 11 4964 8250.
E-mail addresses: mblanco@ffyb.uba.ar, mercedesblanco2@yahoo.com.ar (M.M.
In our first approach (Scheme 1), N-unsubstituted
x-chloroal-
kanamides were subjected to nucleophilic substitution–
a
Blanco).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.088

M. A. Ramírez et al. / Tetrahedron Letters 52 (2011) 1466–1468
1467
Table 1
Compounds 1,2,3 prepared
O
Cl
()n-1
Cl
Compd 1,2,3
n
R1
R2
Overall yields of 1 (%)
O
HO
NR1R2
n = 4
n = 5
()n-1
R1R2NH
a
b
c
d
e
f
g
h
i
4,5
4,5
4,5
4,5
4,5
4,5
4,5
4,5
4,5
4,5
4,5
4,5
C6H5
H
H
H
H
H
H
H
H
69
68
65
67
71
72
73
70
73
63
64
67
66
72
71
74
69
67
67
66
64
65
66
65
4-ClC6H4
2-ClC6H4
4-FC6H4
4-NO2C6H4
4-CH3C6H4
4-CH3OC6H4
3,4-Cl2C6H3
4-ClC6H4CH2
C6H5
NH3
O
Cl
NR1R2
()n-1
2
NaN3
H
O
j
k
l
CH3
C2H5
CH2C6H5
(BH3)2
CH2C6H5
CH2C6H5
N3
H2N
NR1R2
NR1R2
1 (n=4,5)
()n-1
()n-1
3 (n=4,5)
Scheme 2.
O
Cl
()3
Table 2
NH2
Yields (%) of selected compounds 1 using LiAlH4/THF or (BH3)2/THF as a reducing
agent
PhNH2
Conversion
LiAlH4/THF
(BH3)2/THF
3a?1a (n = 4)
3d?1d (n = 4)
3f?1f (n = 4)
3c?1c (n = 5)
3d?1d (n = 5)
3f?1f (n = 5)
52
45
55
40
48
58
75
75
77
77
75
74
O
O
PhHN
PhHN
O
()3
N
NH2
()3 NHPh
Ph
(BH3)2
PhHN
()3
1a (n=4)
NH2
With the aim to optimize the reaction, we used microwave irra-
diation, a valuable technique, which has received increasing atten-
tion in the last decades.13 In DMF at 200 W, 60° (for n = 4) and 70°
(for n = 5), we obtained excellent yields (>90%) in 15–45 min.14
The second step of this synthetic pathway consisted of the
reduction of the azido and amido groups. It is known that most
reducing agents convert the azido group to a primary amino
group.15 Instead, reduction of amides requires more powerful con-
ditions.16 With the aim to achieve the concomitant reduction of
both the groups, we chose lithium aluminum hydride/THF and bor-
ane/THF (Table 2). Although both reducing agents led to diamines
1, the best results were obtained with borane/THF under argon
atmosphere.17 The reduction of both groups occurred in 1.5–2 h
with very good yields.
With the above procedure we obtained the N-aryltetra and pen-
tamethylenediamines 1a–h (Table 1). The method was also appro-
priate to obtain the anisidyl derivatives 1g, whose synthesis failed
with our own previous method11 as a consequence of the presence
of an acid-labile substituent.
In order to explore the generality of the method we synthesized
the N-p-chlorobenzyl derivatives (1i, n = 4,5) with good global
yields.
Scheme 1.
reduction sequence. The strategy involved the generation of the
arylamino group by aminolysis of the haloamides with arylamines
and later reduction of the carboxamide group. In a first assay, the
reaction of 4-chlorobutyramide with aniline leads to N-(4-phe-
nylamino)butyramide, whose reduction with borane afforded dia-
mine 1a (n = 4). However, the overall yield of the synthetic
pathway was low (20%) because the aminolysis step resulted in
formation of the expected product (1a) along with two undesired
compounds: transamidation product and lactam product (N-phen-
ylpyrrolid-2-one), as the result of an intramolecular aminolysis
reaction12 (Scheme 1).
The second approach to obtain diamines 1 involved the use of
N-aryl-x-chloroalkanamides 2 as key intermediates, generating
the arylamino group by reduction of the carboxamide function
and the primary amino group by substitution of the halogen. As
expected, the acylation of different amines with 4-chlorobutyryl
and 5-chlorovaleryl chlorides under standard conditions led to
the isolation of the N-substituted
and complete chemoselectivity (Scheme 2). However, direct
ammonolysis of the chloroamides furnished the expected
aminoamides in low yields, being the corresponding alcohol as
the main product of the reaction. Therefore, to circumvent this
problem, we assayed a variant of this method, which involved
the conversion of the chloroamides 2 into the azidoamides 3 and
further reduction.
x
-chloroamides in good yields
Finally, the method was extended to the synthesis of N,N-disub-
stituted diamines 1j–l. In this case, secondary aromatic amines
such as N-methylaniline and secondary aliphatic amines (ethylb-
enzylamine and dibenzylamine) were used as starting compounds.
It is interesting to highlight that, unlike what is expected due to the
stability of benzyl carbocations,18 no debenzylation was observed
in the decomposition of the B-containing complexes when heating
in hydrochloric acid.
2
Thus, the compounds 2a–h were transformed into the corre-
sponding azidoamides 3 by nucleophilic substitution of the halo-
gen using sodium azide ( Table 1). When the reactions were
carried out in DMF at 60° (for n = 4) and 80° (for n = 5), working
with conventional heating, between 3 and 9 h were required for
total conversion.
In conclusion, we herein present a new method for the synthe-
sis of N-substituted tetra- and pentamethylenediamines using
N-substituted
x-chloroalkanamides as key intermediates. The
method involves the microwave-promoted substitution of the
halogen by azide and later reduction with diborane. The approach
allowed us to obtain N-aryltetra- and pentamethylendiamines

1468
M. A. Ramírez et al. / Tetrahedron Letters 52 (2011) 1466–1468
9. (a) Lu, Z.; Twieg, R. J. Tetrahedron Lett. 2005, 46, 2997; (b) Orelli, L. R.; Salerno,
A.; Hedrera, M. E.; Perillo, I. A. Synth. Commun. 1998, 29, 1625; (c) Orelli, L. R.;
Blanco, M. M.; Garcia, M. B.; Hedrera, M. E.; Perillo, I. A. Synth. Commun. 2001,
31, 685; d Chang, Y. H.; Evanega, G. R.; McLamore, W. M. U.S. Patent 3,729564,
1973, among others.
with the aryl groups containing different substituents (halogens,
nitro, and alkoxy) and was extended to obtain N-benzyl and N,N-
selectively disubstituted derivatives with very good yields.
10. (a) Alonso Garrido, D. O.; Buldain, G.; Frydman, B. J. Org. Chem. 1984, 49, 2021;
(b) Salvatore, R. N.; Schmidt, S. E.; Shin, S. I.; Nagle, A. S.; Worrell, J. H.; Jung, K.
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11. Ramirez, M. A.; Corona, M. V.; Blanco, M. M.; Perillo, I. A.; Porcal, W.; Salerno, A.
Tetrahedron Lett. 2010, 51, 5000. This paper corresponds to Part I of the series..
12. Stirling, C. J. M. J. Chem. Soc. 1958, 4531. and references cited therein..
13. (a)For reviews on microwave chemistry, see: Microwaves in Organic Synthesis;
Loupy, A., Ed.; Wiley-VCH: Weinheim, 2002; (b) Kappe, C. O.; Dallinger, D. Nat.
Rev. Drug Disc. 2006, 5, 55; (c) Roberts, B. A.; Strauss, C. R. Acc. Chem. Res. 2005,
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Acknowledgments
This work was financially supported by the Universidad de Bue-
nos Aires and the Agencia Nacional de Promoción Científica y
Tecnológica.
Supplementary data
14. In a typical reaction, in a 10 mL glass tube were placed the appropriate
chloroamide 2 (1 mmol), sodium azide (2.5 mmol) and DMF (3 mL). The tube
was closed with a septum and placed into the microwave cavity. The reaction
mixture was subjected to microwave irradiation (200 W) 60 °C, 15 min for 3a–
l, n = 4 and 70 °C, 45 min for 3a–l, n = 5. After allowing the mixture to cool to
room temperature, the reaction vessel was opened and the mixture was
poured into ice-water. If the product crystallized, the resulting solid was
filtered, washed with water and purified by recrystallization or by
chromatographic methods. If not, the suspension was extracted with
chloroform and the organic layer was washed with water, dried,
concentrated in vacuo and purified by chromatographic methods.
15. (a) Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 298; (b) Bräse, S.; Gil, C.;
Knepper, K.; Zimmermann, V. Angew. Chem., Int. Ed. 2005, 44, 5188.
16. (a)Reductions in Organic Chemistry; Hudlicky, M., Ed.; John Wiley & Sons: New
York, 1984; (b)Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, UK, 1991; Vol. 8, (c)Reductions by the Alumino and
Borohydrides in Organic Synthesis; Seyden-Penne, J., Ed.; Wiley VCH: New
York, 1997.
17. Compounds 2 (5 mmol) were treated with BH3/THF (10 mL satd soln) and
heated under reflux under argon atmosphere for 1.5–2 h. THF was evaporated
in vacuo and the residue boiled with concentrated hydrochloric acid (10 mL)
for 3 h after which the solution was cooled and allowed to stand at room
temperature for 12 h. The acid solution was diluted with water (5 mL) and then
made alkaline (pH 12) with sodium hydroxide pellets. The mixture was
extracted with ethyl acetate (4 ꢀ 20 mL) and the organic layer was washed
with water (5 mL), dried with anhydrous sodium sulfate, filtered, and
evaporated in vacuo affording the corresponding compounds 1a–l as oils,
which were purified by column chromatography (chloroform/methanol 8:2–
1:1). Reduction with lithium aluminum hydride/THF was carried out according
to the literature procedure19 with minor modifications. Yields are depicted in
Table 2.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.01.088.
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