An Efficient Synthesis of N-Alkyl-N-arylputrescines and Cadaverines

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An Efficient Synthesis of N-Alkyl-N-
arylputrescines and Cadaverines
María C. Molloa, Nadia Grubera, Jimena E. Díaza, Juan Á. Biscegliaa &
Liliana R. Orellia
a Departamento de Química Orgánica. Facultad de Farmacia y
Bioquímica Universidad de Buenos Aires. CONICET. Junín 956,
(1113), Buenos Aires, Argentina
Published online: 15 Sep 2014.
To cite this article: María C. Mollo, Nadia Gruber, Jimena E. Díaz, Juan Á. Bisceglia & Liliana
R. Orelli (2014) An Efficient Synthesis of N-Alkyl-N-arylputrescines and Cadaverines, Organic
Preparations and Procedures International: The New Journal for Organic Synthesis, 46:5, 444-452,
DOI: 10.1080/00304948.2014.944404
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Organic Preparations and Procedures International, 46:444–452, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2014.944404
An Efficient Synthesis of N-Alkyl-N-arylputrescines
and Cadaverines
´
Mar´ıa C. Mollo, Nadia Gruber, Jimena E. D´ıaz, Juan A. Bisceglia,
and Liliana R. Orelli
Departamento de Qu´ımica Orga´nica. Facultad de Farmacia y Bioqu´ımica
Universidad de Buenos Aires. CONICET. Jun´ın 956, (1113) Buenos Aires,
Argentina
N-Substituted 1,4-diaminobutane (putrescine) and 1,5-diaminopentane (cadaverine)
derivatives are of biochemical and pharmacological interest as synthetic analogs of natu-
ral polyamines.1 Several derivatives have been reported to act as antibiotic, anti-neoplastic,
anti-parasitic agents, and NMDA or cholinergic modulators.2–8 In addition, such compounds
represent key intermediates for acyclic and heterocyclic polyamine derivatives.9–12
The methods usually employed for the synthesis of symmetrically N,Nꢀ-disubstituted
1,n-diamines involve functionalization of the parent diamine but cannot be applied to
unsymmetrical derivatives, which require more elaborate strategies.9,13–15 In particular, se-
lectively N-substituted putrescines and cadaverines present a challenge, since the available
methods for di- and trimethylenediamines are not generally suitable for their higher homo-
logues. Several preparations of N-alkyl tetra and pentamethylenediamines have already been
described,16–18 but very few general methods are available for N-aryl derivatives.19–21 The
literature regarding N-alkyl-N-arylputrescines and cadaverines 1 is even scarcer. Recently,
Ram´ırez et al. reported the synthesis of two derivatives, by a three-step strategy starting
from ω−haloalkanoyl chlorides,21 in which the substituted amino group is generated from
an amide, while the primary amine results from reduction of an azide.22
N-Alkylation is conceptually the most straightforward disconnection towards sec-
ondary and tertiary amines.23 Although this transformation seems rather simple, the fact
that the newly formed amines are also nucleophilic brings about the formation of bis-
and/or polyalkylation by-products. Thus, the crude reaction mixture often contains the de-
sired product together with the starting amine and variable amounts of collateral products,
all of them with similar Rf values, a fact that complicates the chromatographic purification
of the desired compounds. In this context, new methodologies combining operational sim-
plicity, high yields, readily available starting materials and low cost reagents are desirable
Received December 13, 2013; in final form May 22, 2014.
Address correspondence to Liliana R. Orelli, Departamento de Qu´ımica Orga´nica. Facultad de
Farmacia y Bioqu´ımica. Universidad de Buenos Aires. CONICET. Jun´ın 956, (1113) Buenos Aires,
Argentina. E-mail: lorelli@ffyb.uba.ar
444

Efficient Synthesis of N-Alkyl-N-arylputrescines and Cadaverines
445
for the high throughput preparation of the target compounds. This work describes a practical
method for the synthesis of tertiary N-alkyl-N-aryltetra- and pentamethylenediamines 3, by
selective monoalkylation of N-alkylanilines with ω−haloalkylnitriles followed by reduc-
tion. The optimized reaction conditions resulted in an efficient procedure, of remarkable
selectivity in the alkylation step and high overall yields of the diamines.
We first examined the synthesis of N-methyl-N-phenylputrescine (3a) using different
reaction conditions for the N-alkylation step. The starting conditions were chosen on the
basis of previous reports on the selective alkylation of amines19,24–26 using equimolar
amounts of the reagents, DMF as the solvent, Cs2CO3 as the base, and KI (2 equiv.). Under
these conditions, the N-alkylated product 3a was obtained in 60% yield. Reduction of the
intermediate aminonitrile with BH3.THF (81%) led to N-methyl-N-phenylputrescine (3a,
49% overall yield from 1a). A significant improvement in the yield of the first step (74%)
was observed employing K2CO3 instead of cesium carbonate as the base (60% overall
yield). Furthermore, TLC analysis of the crude amination product showed the absence of
any bis-alkylation product, thus allowing for its reduction without previous purification.
This led to a further increase in the overall yield (78%), and considerable simplification
of the whole procedure. In fact, the small Rf difference between N-methylaniline and the
aminonitrile complicates its chromatographic purification. In contrast, the crude reduction
product contained only the starting arylamine and the desired compound 3a (ꢀRf > 0.6,
dichloromethane), and was easily purified by short-column filtration. On changing the molar
ratio arylamine:halonitrile from 1:1 to 2:1, a further improvement in the overall yield to
83% was observed. The unreacted arylamine was recovered quantitatively after BH3.THF
treatment.
The use of the optimized experimental conditions (Scheme 1) allowed the preparation
of a series of N-aryl-N-alkylcadaverines and putrescines 3b-m in high overall yields, as
shown in Table 1.
1. K CO , KI
2
3
2. BH THF
3.
a) R = H, Rꢀ = Me, n = 3. b) R = H, Rꢀ = Et, n = 3. c) R = H, Rꢀ = iPr, n = 3. d) R =
4-Cl, Rꢀ = Et, n = 3. e) R = 4-Me, Rꢀ = Et, n = 3. f) R = 2-Me, Rꢀ = Et, n=3. g) R = H,
Rꢀ = Ph, n=3. h) R = H, Rꢀ = Me, n=4. i) R = H, Rꢀ = Et, n=4. j) R = H, Rꢀ = iPr, n=4.
k) R = 4-Cl, Rꢀ = Et, n=4. l) R = 4-Me, Rꢀ = Et, n=4. m) R = 2-Me, Rꢀ = Et, n = 4.
Scheme 1
The results obtained for tertiary amines 3, prompted us to examine the synthesis of
compounds 5 (Scheme 2) using the improved experimental protocol (Table 2). Due to the
higher reactivity of primary arylamines, a 4:1 mixture of DME:DMF was used as the solvent
in the first step. Also in this case, the complete selectivity of the N-monoalkylation step
allowed for the reduction of the crude amination products without purification.

446
Orelli et al.
1. K CO , KI
2
3
2. BH THF
3.
(a) R = H, n = 3. (b) R = 2-Me, n = 3. (c) R = 4-Cl, n = 3. (d) R = 4-Br, n = 3.
(e) R = 4-F, n = 3. (f) R = 4-NO2, n = 3. (g) R = H, n = 4. (h) R = 2-Me, n = 4.
(i) R = 4-Me, n = 4. (j) R = 4-Cl, n = 4. (k) R = 4-Br, n = 4. (l) R = 4-F, n = 4.
Scheme 2
Table 1
Synthesis of N-Alkyl-N-arylputrescines and Cadaverines 3
Cmpd
Yield (%)
mp (◦C)
lit. mp. (◦C)
Temp. (◦C)
3a
3b
3c
3d
3e
3f
3g
3h
3i
83
75
71
64
73
70
8
87
83
77
69
75
71
pale yellow oil
pale yellow oil
pale yellow oil
light brown oil
pale yellow oil
pale yellow oil
pale yellow oil
pale yellow oil
pale yellow oil
pale yellow oil
light brown oil
pale yellow oil
pale yellow oil
oila
—
—
—
—
—
—
oila
oilb
—
—
—
—
100
100
100
110
100
110
110
100
100
100
110
100
110
3j
3k
3l
3m
(a) Lit. mps. from ref. 21. (b) Lit. mp. from ref. 27.
These results (Table 2) constitute a remarkable improvement (about 20% average) in the
yields of compounds 5 compared to those obtained under our previous conditions,19 which
involved a two-step procedure and equimolar amounts of the reagents, DMF as the solvent,
Cs2CO3 as the base, KI (2 equivalents) for the amination reaction followed by chromato-
graphic purification and subsequent reduction.19 The present method is also advantageous
with respect to the alternative synthetic approaches described in the literature,20,21 leading
to improved yields in a minimum number of steps.
In conclusion, we have developed an efficient protocol for the high throughput synthesis
of tertiary N-arylputrescines and cadaverines, which are potentially bioactive as synthetic
analogs of the natural polyamines. The sequence employs readily available and inexpensive
starting materials, and involves two steps and one column purification. It represents an
advantageous alternative to other synthetic approaches21 regarding yields, number of steps
and operational simplicity. The method was successfully adapted to the preparation of

Efficient Synthesis of N-Alkyl-N-arylputrescines and Cadaverines
447
Table 2
Synthesis of N-Arylputrescines and Cadaverines 5
Cmpd
Yielda (%)
mp. (◦C)
lit. mp. (◦C)
Temp. (◦C)
5a
5b
5c
5d
5e
5f
5g
5h
5i
92 (55)
78 (59)
69 (62)
74 (51)
78 (54)
46 (—)
71 (53)
72 (46)
71 (58)
69 (55)
73 (49)
71 (—)
light brown oil
light brown oil
light brown oil
pale yellow oil
light brown oil
oilb
oilb
—
oilb
oilb
101c
oilb
oilb
100
95
100
100
95
100
100
95
c
101–102, orange solid
light brown oil
light brown oil
light brown oil
90–92, pale yellow solid
pale yellow oil
c
—
—
85
c
5j
5k
5l
100
100
95
oilb
oild
light brown oil
(a) Yields from ref. 19 in parenthesis. (b) Lit. mps. from ref. 19. (c) Lit. mps. from ref. 20. (d) Lit.
mps. from ref. 21.
N-arylputrescines and cadaverines 5, key intermediates in the preparation of acyclic and
heterocyclic 1,n-diamine derivatives.
Experimental Section
1H NMR spectra were recorded on a 500 MHz Bruker Avance II 500 spectrometer, in
CDCl3. Chemical shifts are reported in δ (ppm) relative to TMS as an internal standard and
coupling constants are given in Hz. Elemental analyses were determined using an Exeter
CE 440 elemental analyzer. IR spectra were obtained as films on a Perkin-Elmer Spectrum
One FT-IR spectrometer. Reagents, solvents and starting materials were purchased from
standard sources and purified according to literature procedures.29 Potassium iodide was
dried (2 h, 120◦C) prior to use.
Two-step Procedure for the Synthesis of N-methyl-N-phenyl-1,4-butanediamine (3a)
N-Methyl-N-phenyl-4-aminobutyronitrile
A solution of 4-chlorobutyronitrile (258.8 mg, 2.5 mmol) in dimethylformamide (0.5 ml)
was added over 1.5 h to a mixture of N-methylaniline (267.9 mg, 2.5 mmol), K2CO3
(345.5 mg, 2.5 mmol) and KI (830 mg, 5 mmol) in dimethylformamide (3 ml). The mixture
was stirred 5 h at 100◦C. After completion of the reaction, as indicated by TLC, the mixture
was treated with ethyl ether (50 ml) and water (10 ml). The aqueous phase was separated and
extracted with ethyl ether (30 ml). The combined organic layers were dried over anhydrous
sodium sulfate and filtered. The solvent was evaporated in vacuo. The crude product
was purified by column chromatography (silica gel, hexane:chloroform 3:7) to furnish
322 mg (74%) of N-methyl-N-phenyl-4-aminobutyronitrile as a pale yellow oil. 1H NMR:

448
Orelli et al.
δ 7.25-7.28 (2H, m), 6.74–6.77 (3H, m), 3.47 (2H, t, J = 7.0), 2.96 (3H, s), 2.39 (2H, t,
J = 7.0), 1.95 (2H, p, J = 7.0). 13C NMR: δ 148.88, 129.26, 119.33, 117.00, 112.56, 51.17,
38.68, 23.02, 14.63. IR: 2967, 2959, 2254, 1722, 1596 cm−1
.
Anal. Calcd for C11H14N2: C, 75.82; H, 8.10; N, 16.08. Found: C, 75.78; H, 8.03; N,
15.98.
Under identical experimental conditions, but using Cs2CO3 instead of K2CO3 as the
base, N-methyl-N-phenyl-4-aminobutyronitrile was obtained in 60% yield.
N-Methyl-N-phenyl-1,4-butanediamine (3a)
N-Methyl-N-phenyl-4-aminobutyronitrile (348.5 mg, 2 mmol) was treated with 1M bo-
rane/THF (30 ml). The solution was refluxed for 2 h, cooled and treated with methanol. The
solvent was then evaporated in vacuo. The residue was refluxed with 10% hydrochloric
acid (30 ml) for 2 h, filtered and made alkaline with 10% aqueous sodium hydroxide.
The alkaline mixture was extracted with ethyl acetate (4 × 20 ml). The organic phase
was washed with water (5 ml), dried over sodium sulfate and filtered. The solvent was
evaporated in vacuo and the resulting crude liquid was purified by column chromatog-
raphy (silica gel, dichloromethane:methanol:isopropylamine 10:1:0.1) to provide 288 mg
(81%) of N-methyl-N-phenyl-1,4-butanediamine (3a) as a pale yellow oil. Compound 3a
has been described and its characterization data match those previously reported in the
literature.21
General Procedure for the Synthesis of N-Alkyl-N-arylputrescines and Cadaverines (3)
and N-Arylputrescines and Cadaverines (5).
A solution of the corresponding ω−halonitrile (2.5 mmol) in dimethylformamide (0.5 ml)
was added over 1.5 h to a mixture of the arylamine (5 mmol), K2CO3 (345.5 mg, 2.5 mmol)
and KI (830 mg, 5 mmol) in dimethylformamide (3 ml) for compounds 1 or dimethyl-
formamide (0.6 ml) and dimethoxyethane (2.4 ml) for compounds 4. The mixture was
stirred at the indicated temperature for 5 h. After completion of the reaction, as indicated
by TLC, the mixture was diluted with ethyl ether (50 ml) and water (10 ml). The aqueous
phase was separated and additionally extracted once with ethyl ether (30 ml). The com-
bined organic layers were washed with water, dried over anhydrous sodium sulfate and
filtered. The filtrate was evaporated in vacuo and the resulting crude material was dissolved
in tetrahydrofuran and treated with 1M borane/THF (30 ml). The solution was refluxed
for 2 h, cooled and treated with methanol. The solvent was then evaporated in vacuo.
The residue was refluxed with 10% hydrochloric acid (30 ml) for 2 h, filtered and made
alkaline with 10% aqueous sodium hydroxide. The alkaline mixture was extracted with
ethyl acetate (4 × 20 ml). The organic phase was washed with water (5 ml), dried over
sodium sulfate and filtered. The solvent was evaporated in vacuo and the crude product was
purified by column chromatography (silica gel, dichloromethane:methanol:isopropylamine
10:1:0.1).
Compounds 3h,21 3i,27 5a, 5b, 5d, 5e, 5h,19 5c, 5h, 5i, 5j,20 5k,11 5l,20 5f28 have been
described in the literature, and their physical and spectroscopic data match those previously
reported in the literature.11,19–21,27,28 The characterization of new compounds is reported
below.

Efficient Synthesis of N-Alkyl-N-arylputrescines and Cadaverines
N-Ethyl-N-phenyl-1,4-diaminobutane (3b)
449
This compound was obtained as a pale yellow oil. 1H NMR: δ 7.20–7.25 (2H, m), 6.70-6.69
(2H, m), 6.65 (1H, tt, J = 7.2, 1.0), 3.38 (2H, q, J = 7.0), 3.28 (2H, t, J = 7.7), 2.74 (2H, t,
J = 7.1), 2.01(2H, bs), 1.63 (2H, p, J = 7.7), 1.50–1.56 (2H, m), 1.35–1.43 (2H, m), 1.17
(3H, t, J = 7.1). 13C NMR: δ 147.89, 129.18, 115.29, 111.77, 50.26, 44.88, 41.94, 33.22,
27.35, 24.43, 12.23.
Anal. Calcd for C12H20N2: C, 74.95; H, 10.48; N, 14.57. Found: C, 74.82; H, 10.57;
N, 14.49.
N-Isopropyl-N-phenyl-1,4-diaminobutane (3c)
This compound was obtained as a pale yellow oil. 1H NMR: δ 7.22-7.26 (2H, m), 6.77 (2H,
d, J = 8.0), 6.70 (1H, tt, J = 7.2, 0.9), 4.06 (1H, h, J = 6.6), 3.15 (2H, t, J = 7.8), 2.75
(2H,t,7.0), 1,73 (2H, bs), 1.58-1.64 (2H, m), 1.47–1.55 (2H, m), 1.2 (6H, d, J = 6.6). 13C
NMR: δ 148.75, 129.16, 116.2, 113.54, 48.79, 43.80, 42.08, 31.38, 26.70, 20.10. IR: 3345,
3058, 3021, 2968, 1597 cm−1
Anal. Calcd for C13H22N2: C, 75.68; H, 10.75; N, 13.58. Found: C, 75.58; H, 10.89;
N, 13.50.
.
N-Ethyl-N-(4-chlorophenyl)-1,4-diaminobutane (3d)
This compound was obtained as a light brown oil. 1H NMR: δ 7.14 (2H, dd, J = 9.2, 3.5),
6.58 (2H, dd, J = 9.2, 3.4), 3.35 (2H, q, J = 7.1), 3.26 (2H, t, J = 7.3), 2.76 (2H, t, J = 7.1),
2.16 (2H, bs), 1.58–1.66 (2H, m), 1.48–1.55 (2H, m), 1.14 (3H, t, J = 7.1); 13C NMR: δ
146.42, 128.93, 120.10, 112.98, 50.32, 45.13, 41.81, 30.69, 24.79, 12.10. IR: (3404, 2969,
2933, 2869, 1596, 1563, 1500 cm−1
Anal. Calcd for C12H19ClN2: C, 63.56; H, 8.45; N, 12.35. Found: C, 63.46; H, 8.60;
N, 12.27.
.
N-Ethyl-N-(4-methylphenyl)-1,4-diaminobutane (3e)
This compound was obtained as a pale yellow oil. 1H NMR: δ 7.03 (2H, d, J = 8.6), 6.62
(2H, d, J = 8.6), 3.33 (2H, q, J = 7.0), 3.24 (2H, t, J = 7.5), 2.74 (2H, t, J = 7.1), 2.25 (3H,
s), 2.06 (2H, bs), 1.58–1.65 (2H, m), 1.46-1.54 (2H, m), 1.13 (3H, t, J = 7.0); 13C NMR: δ
145.81, 129.70, 124.80, 112.49, 50.39, 45.19, 41.92, 30.94, 24.89, 20.10, 12.21. IR: 3321,
2966, 2930, 2864, 1618, 1568 cm−1
Anal. Calcd. for C13H22N2: C, 75.68; H, 10.75; N, 13.58. Found: C, 75.61; H, 10.88;
N, 13.51.
.
N-Ethyl-N-(2-methylphenyl)-1,4-diaminobutane (3f)
1
This compound was obtained as a pale yellow oil. H NMR: δ 7.18 (1H, d, J = 7.5),
7.12–7.16 (1H, m), 7.07 (1H, dd, J = 7.8, 1.1), 6.98 (1H, td, J = 7.3, 1.4), 2.95 (2H, t, J
= 7.0)∗, 2.96 (2H, q, J = 7.1)∗, 2.65–2.67 (2H, m), 2.29 (3H, s), 2.08 (2H, bs), 1.41–1.47
(4H, m), 0.98 (3H, t, J = 7.1) ∗: overlapping signals; 13C NMR: δ 149.84, 135.08, 130.84,
125.94, 123.16, 122.11, 52.60, 48.40, 41.85, 31.05, 24.70,18.24, 12.18. IR: 3346, 3017,
2967, 1597, 1491, cm−1
.

450
Orelli et al.
Anal. Calcd. for C13H22N2: C, 75.68; H, 10.75; N, 13.58. Found: C, 75.59; H, 10.91;
N, 13.50.
N,N-Diphenyl-1,4-diaminobutane (3g)
1
This compound was obtained as a pale yellow oil. H NMR: δ 7.26–7.30 (4H, m), 7.00
(4H, d, J = 7.8), 6.96 (2H, t, J = 7.3), 3.73 (2H, t, J = 7.6), 3.42 (2H, bs), 2.77 (2H, t, J =
7.2), 1.70–1.76 (2H, m), 1.57–1.63 (2H, m); 13C NMR: δ 147.89, 129.25, 121.19, 120.88,
51.93, 41.38, 29.64, 24.83. IR: 3357, 3034, 2932, 1588 cm−1
Anal. Calcd. for C16H20N2: C, 79.96; H, 8.39; N, 11.66. Found: C, 79.89; H, 8.42; N,
11.61.
.
N-Isopropyl-N-phenyl-1,5-diaminopentane (3j)
1
This compound was obtained as a pale yellow oil. H NMR: δ 7.22–7.26 (2H, m), 6.76
(2H, d, J = 8.0), 6,69 (1H, tt, J = 7.32, 1.0), 4.06 (1H, h, J = 6.6), 3.14 (2H, t, J = 7.9),
2.74 (2H, t, J = 7.0), 1.77 (2H, bs), 1.58–1,64 (2H, m), 1.53 (2H, p, J = 7.3), 1.36–1.42
(2H, m), 1,20 (6H, d, J = 6.6). 13C NMR: δ 148.71, 129.07, 115.95, 113.25, 48.55, 43.84,
42.07, 33.37, 29.11, 24.50, 20.01. IR: 3405, 2968, 2934, 2868, 1597 cm−1
.
Anal. Calcd. for C14H24N2: C, 76.31; H, 10.98; N, 12.71. Found: C, 76.25; H, 11.10;
N, 12.66.
N-Ethyl-N-(4-chlorophenyl)-1,5-diaminopentane (3k)
This compound was obtained as a light brown oil. 1H NMR δ: 7.13 (2H, dd, J = 9.2, 3.5),
6.56 (2H, dd, J = 9.2, 3.5), 3.32 (2H, q, J = 7.0), 3.24 (2H, t, J = 7.7), 2.72 (2H, t, J =
7.2), 2.26 (2H, bs), 1.55–1.62 (2H, m), 1.49–1.55 (2H, m), 1.32–1.39 (2H, m), 1.12 (3H, t,
J = 7.0); 13C NMR δ: 146.48, 128.92, 120.00, 112.91, 50.42, 45.09, 41.82, 32.93, 27.21,
24.38, 12.10. IR: 3422, 2970, 2934, 1636, 1596 cm−1
.
Anal. Calcd. for C13H21ClN2: C, 64.85; H, 8.79; N, 11.63. Found: C, 64.79; H, 8.86;
N, 11.61.
N-Ethyl-N-(4-methylphenyl)-1,5-diaminopentane (3l)
This compound was obtained as a pale yellow oil. 1H NMR: δ 7.03 (2H, d, J = 8.5), 6.61
(2H, d, J = 8.5), 3.33 (2H, q, J = 7.1), 3.22 (2H, t, J = 7.6), 2.73 (2H, t, J = 7.1), 2.52
(2H, bs), 2.25 (3H, s), 1.56–1.62 (2H, m), 1.49-1.55 (2H, m), 1.34-1.40 (2H, m), 1.13 (3H,
t, J = 7.1); 13C NMR: δ 145.87, 129.68, 124.64, 112.36, 50.47, 45.10, 41.75, 32.87, 27.33,
24.43, 20.10, 12.20. IR: 3338, 2966, 2931, 2860, 1618 cm−1
.
Anal. Calcd. for C14H24N2: C, 76.31; H, 10.98; N, 12.71. Found: C, 76.27; H, 11.07;
N, 12.68.
N-Ethyl-N-(2-methylphenyl)-1,5-diaminopentane (3m)
1
This compound was obtained as a pale yellow oil. H NMR: δ 7.18 (1H, d, J = 7.6),
7.12-7.16 (1H, m), 7.07 (1H, dd, J = 7.8, 1.0), 6.97 (1H, td, J = 7.3, 1.4), 2.95 (2H, q, J
= 7.1)∗, 2.92–2.95 (2H, m)∗, 2.65 (2H, t, J = 7.1), 2.29 (3H, s), 2.00 (2H, bs), 1.39–1.45
(4H, m), 1.27-1.33 (2H, m), 0.98 (3H, t, J = 7.1); 13C NMR: δ:149.98, 135.07, 130.81,

Efficient Synthesis of N-Alkyl-N-arylputrescines and Cadaverines
451
125.91, 123.09, 122.12, 52.81, 48.37, 41.96, 33.18, 27.16, 24.51, 18.24, 12.22. IR: 3422,
2969, 2939, 2858, 1639, 1598 cm−1
Anal. Calcd. for C14H24N2: C, 76.31; H, 10.98; N, 12.71. Found: C, 76.28; H, 11.04;
N, 12.69.
.
Acknowledgement
This work was supported by the University of Buenos Aires (N◦ 20020100100935) and by
CONICET (PIP 286).
References
1. M. R. Burns, US Patent 6, 872, 852. (2005).
2. B. J. Frydman, US Patent 5, 677, 350. (1997).
3. B. J. Frydman and A. Valasinas, Exp. Opin. Ther. Patents, 9, 1055 (1999).
4. A. I. Sacaan and K. M. Johnson, J. Pharmacol. Exp. Ther., 255, 1060 (1990).
5. M. V. N. de Souza, K. C. Pais, C. R. Kaiser, M. A. Peralta, M. L. Ferreira and M. C. S. Lourenc¸o,
Bioorg. Med. Chem., 17, 1474 (2009).
6. G. R. Labadie, S.-R. Choi and M. A. Avery, Bioorg. Med. Chem., 14, 615 (2003).
7. M. Iwata, M. Izawa, N. Sasaki, Y. Nagumo, H. Sasabe and Y. Hayashizaki, Bioorg. Med. Chem.,
8, 2185 (2000).
8. A. P. Caminos, E. A. Panozzo-Zenere, S. R. Wilkinson, B. L. Tekwani and G. R. Labadie, Bioorg.
Med. Chem. Lett., 22, 1712 (2012).
9. L. R. Orelli, A. Salerno, M. E. Hedrera and I. A. Perillo, Synth. Commun., 28, 1625 (1998).
10. M. B. Garc´ıa, R. A. Torres and L. R. Orelli, Tetrahedron Lett., 47, 4857 (2006).
11. J. E. D´ıaz, N. Gruber and L. R. Orelli, Tetrahedron Lett., 52, 6443 (2011).
12. J. A. Bisceglia, J. E. D´ıaz, R. A. Torres and L. R. Orelli, Tetrahedron Lett., 52, 5238 (2011).
13. Z. Lu and R. J. Twieg, Tetrahedron Lett., 46, 2997 (2005).
14. L. R. Orelli, M. M. Blanco, M. B. Garc´ıa, M. E. Hedrera and I. A. Perillo, Synth. Commun., 31,
685 (2001).
15. Y. H. Chang, G. R. Evanega and W. M. McLamore, US Patent 3, 729564. (1973).
16. D. O. Alonso Garrido, G. Y. Buldain and B. J. Frydman, J. Org. Chem., 49, 2021 (1984).
17. R. N. Salvatore, S. E. Schmidt, S. I. Shin, A. S. Nagle, J. H. Worrell and K. W. Jung, Tetrahedron
Lett., 41, 9705 (2000).
18. M. Khoukhi, M. Vaultier, A. Benalil and B. Carboni, Synthesis, 483 (1996).
19. N. P. Link, J. E. D´ıaz and L. R. Orelli, Synlett, 751 (2009).
20. M. A. Ram´ırez, M. V. Corona, M. M. Blanco, I. A. Perillo, W. Porcal and A. Salerno, Tetrahedron
Lett., 38, 5000 (2010).
21. M. A. Ram´ırez, M. V. Corona, G. Ortiz, A. Salerno, I. A. Perillo and M. M. Blanco, Tetrahedron
Lett., 52, 1466 (2011).

452
Orelli et al.
22. A. Paczal, A. C. Be´nyei and A. Kotschy, J. Org. Chem., 71, 5969 (2006).
23. R. N. Salvatore, C. H. Yoon and K. W. Jung, Tetrahedron, 57, 7785 (2001).
24. R. N. Salvatore, A. S. Nagle, S. E. Schmidt and K. W. Jung, Org. Lett., 1, 1893 (1999).
25. R. N. Salvatore, S. E. Schmidt, S. I. Shin, A. S. Nagle, J. H. Worrell and K. W. Jung, Tetrahedron
Lett., 41, 9705 (2000).
26. R. N. Salvatore, A. S. Nagle and K. W. Jung, J. Org. Chem., 67, 674 (2002).
27. K.-J. Hoffmann, P. Stenberg, C. Ljunggren, U. Svensson, J. L. G. Nilsson, O. Eriksson, A.
Hartkoorn and R. Lunde´n, J. Med. Chem., 18, 278 (1975).
28. I. Perillo, B. Fernandez and S. Lamdan, J. Chem. Soc. Pt 2, 2068 (1977).
29. W. L. F. Armarego and C. L. L. Chai, Purification of Laboratory Chemicals, 6th Ed., Elsevier
2009.