An efficient synthesis of N-arylputrescines and cadaverines

Article abstract of DOI:10.1055/s-0028-1087817

We present a two-step, general synthesis of N-aryl-putrescines and cadaverines, by cesium carbonate mediated alkylation of anilines with ω-chloronitriles and subsequent reduction. The cesium-mediated alkylation shows remarkable selectivity towards the mon

Full text of DOI:10.1055/s-0028-1087817

LETTER
751
An Efficient Synthesis of N-Arylputrescines and Cadaverines
N
-Arylputrescines
a
and Cadav
t
Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, CONICET, Junín 956,
1113 Buenos Aires, Argentina
Fax +54(11)49648250; E-mail: lorelli@ffyb.uba.ar
Received 9 July 2008
followed by its photoinduced decomposition, leading to
low yields (43%) of N-phenylputrescine.6 Direct nucleo-
philic substitution of reactive aryl halides with a large ex-
cess of putrescine was alternatively applied for the
Abstract: We present a two-step, general synthesis of N-aryl-
putrescines and cadaverines, by cesium carbonate mediated alkyla-
tion of anilines with w-chloronitriles and subsequent reduction. The
cesium-mediated alkylation shows remarkable selectivity towards
the monoalkylation product. The method is straightforward and synthesis of ortho- or para-nitro aryl derivatives.7 Palladi-
um-catalyzed N-monoarylation8a–8c of diamines8d is an
leads to satisfactory global yields.
alternative methodology which could, in principle,
circumvent these limitations. However, it is at present
restricted to ethylene and propylenediamines, where
the formation of an intramolecular hydrogen bond in the
N-monoarylalkylenediamine prevents the formation of
undesired N,N¢-diarylated product.8d
Key words: alkylations, amines, cesium, nitriles, nitrogen
Naturally occurring polyamines (putrescine, spermine,
and spermidine) are present in virtually all living cells and
are essential for the normal progression of cell cycles.1 Al-
though their functions are not completely clear, abnormal
levels of polyamines are often associated with tumor ini-
tiation and growth.2 In particular, the 1,4-butanediamine
(putrescine) and the homologous cadaverine (1,5-pen-
tanediamine) moieties are found in biologically active
compounds, like antibiotics, antineoplastics, and NMDA
or cholinergic modulators.3 This makes them attractive
targets for the design of biologically active compounds.
As part of our research on nitrogen heterocycles4 we re-
cently needed to prepare some N-aryl-N¢-acylputrescines
as precursors of tetrahydrodiazepines.4f At variance with
1,3-propanediamine derivatives, such precursors cannot
be prepared by aminolysis of N-(4-bromoalkyl)amides.
The von Braun degradation of N-benzoylpyrrolidines fol-
lowed by aminolysis with arylamines was reported as an
alternative synthesis.5 However, this method lacks gener-
ality, as it is restricted to N-acyl moieties without a-hydro-
gens. Besides, it involves the employment of hazardous
phosphorus pentachloride and leads in general to modest
global yields (39–53%) of the desired compounds.5
Considering the virtual absence of a general synthesis of
N-arylputrescines, and in view of their possible applica-
tions as key synthetic intermediates for acyclic and het-
erocyclic tetramethylenediamine derivatives, we present
here a straightforward method for their preparation, which
was extended to N-arylcadaverines. The sequence is de-
picted in Scheme 1 and involves aminolysis of w-chlo-
robutyro (or valero)nitrile with arylamines followed by
reduction of the resulting w-arylaminonitriles. In general,
alkylation of primary arylamines lacks selectivity, leading
to variable amounts of bis- or polyalkylation products.9 In
order to achieve good yields, an excess of the amine is re-
quired,10 although this complicates the purification of the
desired products on a preparative laboratory scale. In re-
cent years, some methods which employ cesium bases
have been successfully applied to the selective alkylation
of primary and secondary alkylamines among other syn-
thetically useful transformations.11 The observed selectiv-
ity was attributed to the so-called ‘cesium effect’,12
critically reviewed by C. Galli.13 The potential application
of cesium bases to the synthesis of secondary arylamines
was not yet investigated. This led us to explore the use of
cesium carbonate as the base for the aminolysis reaction,
employing equimolar amounts of arylamine and halogen
derivative.
In this context, selective monoacylation of N-aryl-
putrescines seemed an interesting alternative for the prep-
aration of the desired compounds. An examination of the
literature revealed a surprising lack of general methods for
the synthesis of the required N-monosubstituted diamines.
Abd-El-Aziz reported a single example of the reaction be-
tween putrescine and a dicyclopentadienyl iron complex
We examined first the reaction between aniline and 4-
chlorobutyronitrile (1:1 molar ratio) in the presence of ce-
ArNH2, Cs2CO3
BH3, THF
( )n
Cl
CN
( )n
ArHN
CN
( )n+1
ArHN
NH2
2
1
Scheme 1
SYNLETT 2009, No. 5, pp 0751–0754
x
x.
x
x.
2
0
0
9
Advanced online publication: 16.02.2009
DOI: 10.1055/s-0028-1087817; Art ID: S06408ST
© Georg Thieme Verlag Stuttgart · New York

752
N. P. Link et al.
LETTER
sium carbonate under different experimental conditions
(Table 1). Using DMF as the solvent, the reaction led to
low yields of monoalkylated product, even in forcing con-
ditions (5 h, 120 °C). The addition of sodium iodide sig-
nificantly improved the reaction yield, without affecting
its selectivity towards the monoalkylated product (entry
2). Such effect may be attributed to the formation of the
more reactive 4-iodobutyronitrile as intermediate. The na-
ture of the iodide counterion was also important for the
outcome of the reaction (entries 2–5). Potassium iodide
was slightly more efficient than the sodium salt, while em-
ployment of cesium or tetrabutylammonium counterions
resulted in a dramatic decrease of the reaction yield. The
optimum molar ratio of aniline to KI was 1:2, and DMF
(polar, aprotic) was more efficient than n-butanol (polar,
protic) as the solvent. Finally, the reaction was attempted
in the absence of cesium carbonate, but the yield was sig-
nificantly lower and bisalkylation product was observed.
Table 2 Alkylation of Anilines with w-Chloronitriles
Cs2CO3
2 KI
DMF
( )n
CN
2
( )n
ArNH2
Cl
CN +
ArHN
Compd 2 Ar
n
1
1
1
1
1
1
1
2
2
2
2
Temp (°C) Time (h) Yield (%)a
2b
2c
2d
2e
2f
4-BrC6H4
4-FC6H4
100
95
4
4
3
4
4
3
3
4
5
4
4
62
66
94
75
81
89
90
65
61
76
72
4-MeC6H4
2-MeC6H4
1-C10H7
75
115
105
75
2g
2h
2i
4-MeOC6H4
3,4-(MeO)2C6H3
Ph
70
95
Table 1 Optimization of the Reaction Conditions
2j
2-MeC6H4
4-MeOC6H4
3,4-(MeO)2C6H3
115
75
NH2
Cs2CO3
additive
solvent
2k
2l
+
CN
NH
CN
Cl
75
2a
a Yields correspond to pure compounds.
Entry Additive
Solvent
DMF
Temp (°C) Time (h) Yield (%)a
Reduction of compound 2a was first attempted with lithi-
um aluminium hydride in dry THF, but the starting mate-
rial was recovered unreacted. This lack of reactivity
towards reduction had previously been observed by us for
N-aryl-N¢-acyltrimethylenediamines,15 and may be related
to the presence of the arylamino moiety. Reduction of
compounds 2a–l was achieved using borane in THF,16
leading to good yields (72–83%) of the desired N-aryl-
putrescines and cadaverines 1 (Table 3).
1
2
3
4
5
6
7
8c
–
110
95
5
4
4
4
4
4
5
5
32
NaI
KI
DMF
60
DMF
95
63
CsI
TBAI
2 KI
2 KI
2 KI
DMF
95
31
DMF
95
trace
68
DMF
95
47b
21d
In conclusion, we have developed a simple and efficient
two-step synthesis of N-arylputrescines and cadaverines
employing readily available and inexpensive starting ma-
terials. This synthetic approach, although simple, had not
been attempted before. To our knowledge, this is the first
general method for the preparation of the desired com-
pounds and also the first report on a cesium carbonate me-
diated monoalkylation of arylamines with equimolar
amounts of the reagents. Further studies on the scope of
the method are in progress.
n-BuOH
DMF
reflux
110
a Yields correspond to pure compound 2a.
b N,N-Bis(3-cyanopropyl)aniline (3a) was isolated in 11% yield.
c The reaction was run in the absence of Cs2CO3.
d Compound 3a was isolated in 9% yield.
Employing the optimized reaction conditions,14 aminoly-
sis of 4-chlorobutyronitrile with different arylamines af-
forded the desired products 2b–h with good to high yields
(Table 2). The optimum reaction temperatures varied ac-
cording to the nucleophilicity of the arylamine. In general,
more reactive substrates required lower reaction tempera-
tures and afforded better yields.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
In view of these encouraging results, we attempted next
the alkylation of different arylamines with 5-chlorovalero-
nitrile. The corresponding 5-arylaminovaleronitriles 2i–l
were obtained with good selectivity, but with lower yields
(Table 2). The same trends regarding reactivity as in the
previous series were in general observed.
This work was supported by the University of Buenos Aires and by
CONICET. We are also grateful to Ms. Romina A. Torres for tech-
nical collaboration.
Synlett 2009, No. 5, 751–754 © Thieme Stuttgart · New York

LETTER
N-Arylputrescines and Cadaverines
753
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Table 3 Reduction of Compounds 2
BH3, THF
NH2
( )n
( )n
CN
ArHN
ArHN
2
1
Compd 1
1a
n
1
1
1
1
1
1
1
1
2
2
2
2
Ar
Yield (%)a
Ph
80
83
82
79
78
72
81
79
82
75
81
79
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1c
4-BrC6H4
4-FC6H4
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1d
1e
4-MeC6H4
2-MeC6H4
1-C10H7
1f
1g
4-MeOC6H4
3,4-(MeO)2C6H3
Ph
1h
1i
1j
2-MeC6H4
4-MeOC6H4
3,4-(MeO)2C6H3
1k
1l
a Yields correspond to pure compounds.
(12) Kruizinga, W. H.; Kellog, R. M. J. Am. Chem. Soc. 1981,
103, 5183.
(13) Galli, C. Org. Prep. Proced. Int. 1992, 24, 285.
(14) Representative Procedure for the Synthesis of
Compounds 2
References and Notes
(1) (a) Cohen, S. S. A Guide to Polyamines; Oxford University
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Mol. Life Sci. 2001, 58, 244.
(2) Bachrach, U. Polyamines in Cancer: Basic Mechanisms and
Clinical Approaches; Landes Bioscience Publishers: Austin,
TX, 1996.
A solution of 4-chlorobutyronitrile (2.5 mmol) in DMF
(1 mL) was added during 1.5 h to a mixture of aniline (2.5
mmol), Cs2CO3 (2.5 mmol), and KI (5 mmol) in DMF
(4 mL). The mixture was stirred 2.5 h at 95 °C. After
completion of the reaction, as indicated by TLC, the mixture
was treated with Et2O (50 mL) and H2O (10 mL). The
aqueous phase was separated and extracted with Et2O (30
mL). The combined organic layers were dried over anhyd
Na2SO4 and filtered. The solvent was evaporated in vacuo.
The crude product was purified by column chromatography
(SiO2, hexane–CHCl3) to furnish 4-(phenylamino)butyro-
nitrile in 69% yield as an oil.
Spectral and Analytical Data for Selected Compounds
4-(Phenylamino)butyronitrile (2a) was obtained as an oil
(69%). 1H NMR (300 MHz, CDCl3): d = 7.17–7.22 (2 H, m),
6.74 (1 H, dt, J = 7.4, 1.0 Hz), 6.61 (2 H, dd, J = 8.8, 1.0 Hz),
3.68 (1 H, br s), 3.33 (2 H, t, J = 6.7 Hz), 2.49 (2 H, t, J = 7.0
Hz), 1.93–2.02 (2 H, m). 13C NMR (75 MHz, CDCl3): d =
147.63, 129.43, 119.50, 117.91, 112.87, 42.31, 25.26, 14.81.
Anal. Calcd for C10H12N2: C, 74.97; H, 7.55; N, 17.48.
Found: C, 74.87; H, 7.65; N, 17.42.
(3) (a) Frydman, B.; Valasinas, A. Expert Opin. Ther. Pat. 1999,
9, 1055. (b) Aizencang, G.; Harari, P.; Buldain, G.; Guerra,
L.; Pickart, M.; Hernández, P.; Frydman, B. Cell. Mol. Biol.
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(d) Sacaan, A. I.; Johnson, K. M. J. Pharmacol. Exp. Ther.
1990, 255, 1060. (e) McGurk, J. F.; Bennett, M. V. L.;
Zukin, R. S. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 9971.
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3, 951. (g) Bergeron, R. J.; Yao, G. W.; Yao, H.; Weimar,
W. R.; Sninski, C. A.; Raisler, B.; Feng, Y.; Wu, Q.; Gao, F.
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(4) (a) Orelli, L. R.; García, M. B.; Perillo, I. A. Heterocycles
2000, 53, 2437. (b) García, M. B.; Grilli, S.; Lunazzi, L.;
Mazzanti, A.; Orelli, L. J. Org. Chem. 2001, 66, 6679.
(c) García, M. B.; Grilli, S.; Lunazzi, L.; Mazzanti, A.;
Orelli, L. Eur. J. Org. Chem. 2002, 4018. (d) García, M. B.;
Orelli, L. R.; Magri, M. L.; Perillo, I. A. Synthesis 2002,
2687. (e) Magri, M. L.; Vanthuyne, N.; Roussel, C.; García,
M. B.; Orelli, L. R. J. Chromatorgr., A 2005, 1069, 203.
(f) García, M. B.; Torres, R. A.; Orelli, L. R. Tetrahedron
Lett. 2006, 47, 4857.
N,N-Bis(3-cyanopropyl)aniline (3a) was obtained as an oil.
1H NMR (300 MHz, CDCl3): d = 7.24–7.27 (3 H, m), 6.80
(1 H, t, J = 7.3 Hz), 6.75 (2 H, d, J = 8.0 Hz), 3.44 (4 H, t,
J = 7.1 Hz), 2.38 (4 H, t, J = 7.0 Hz), 1.90–1.96 (4 H, m). 13
C
(5) Hedrera, M. E.; Perillo, I. A. J. Heterocycl. Chem. 2000, 37,
1431.
(6) Abd-El-Aziz, A.; Bernardin, S. A.; Tran, K. Tetrahedron
Lett. 1999, 40, 1835.
(7) Perillo, I. A.; Fernández, B. M.; Lamdan, S. J. Chem. Soc.,
Perkin Trans. 2 1977, 2068.
NMR (75 MHz, CDCl3): d = 147.08, 129.64, 119.28, 118.30,
114.10, 50.26, 23.09, 14.73. Anal. Calcd for C14H17N3: C,
73.98; H, 7.54; N, 18.49. Found: C, 73.84; H, 7.59; N, 18.51.
5-(Phenylamino)valeronitrile (2i) was obtained as an oil
(65%). 1H NMR (300 MHz, CDCl3): d = 7.18–7.21 (2 H, m),
Synlett 2009, No. 5, 751–754 © Thieme Stuttgart · New York

754
N. P. Link et al.
LETTER
6.72 (1 H, dt, J = 7.0, 1.0 Hz), 6.60 (2 H, dd, J = 8.7, 1.0 Hz),
3.62 (1 H, br s), 3.18 (2 H, t, J = 6.5 Hz), 2.40 (2 H, t, J = 6.8
Hz), 1.71–1.89 (4 H, m). Anal. Calcd for C11H14N2: C, 75.82;
H, 8.10; N, 16.08. Found: C, 75.76; H, 8.14; N, 16.10.
(80%). 1H NMR (300 MHz, CDCl3): d = 7.15–7.20 (2 H, m),
6.69 (1 H, tt, J = 7.3, 1.0 Hz), 6.60 (2 H, td, J = 7.5, 1.0 Hz),
3.13 (2 H, t, J = 6.8 Hz), 2.77 (2 H, t, J = 6.7 Hz), 2.45 (2 H,
br s), 1.56–1.70 (4 H, m). 13C NMR (75 MHz, CDCl3): d =
148.37, 129.19, 117.17, 112.69, 43.72, 41.64, 30.63, 26.83.
Anal. Calcd for C10H16N2: C, 73.13; H, 9.82; N, 17.06.
Found: C, 73.06; H, 9.85; N, 17.01.
N-(Phenyl)-1,5-pentanediamine (1i) was obtained as an oil
(82%). 1H NMR (300 MHz, CDCl3): d = 7.14–7.17 (2 H, m),
6.68 (1 H, dt, J = 7.9, 0.9 Hz), 6.60 (2 H, dd, J = 7.9, 0.9 Hz),
3.11 (2 H, t, J = 7.0 Hz), 2.71 (2 H, t, J = 6.7 Hz), 1.85 (2 H,
br s), 1.53–1.70 (4 H, m), 1.37–1.52 (2 H, m). 13C NMR (75
MHz, CDCl3): d = 144.90, 125.68, 113.59, 109.13, 40.33,
38.41, 29.71, 25.85, 20.90. Anal. Calcd for C11H18N2: C,
74.11; H, 10.18; N, 15.71. Found: C, 74.01; H, 10.21; N,
15.67.
(15) Orelli, L. R.; Salerno, A.; Hedrera, M. E.; Perillo, I. A. Synth.
Commun. 1998, 28, 1625.
(16) General Procedure for the Synthesis of Compounds 1
A solution of compound 2 (2 mmol) in THF (60 mL) was
treated with with freshly generated borane. The solution was
refluxed for 1 h, cooled, and treated with MeOH. The solvent
was then eliminated in vacuo. The residue was refluxed with
10% HCl (60 mL), filtered and made alkaline with 10% aq
NaOH. The alkaline mixture was extracted with CH2Cl2
(2 × 40 mL). The organic phase was washed with H2O (10
mL), dried over Na2SO4, and filtered. The solvent was
eliminated in vacuo. The crude product was purified by
column chromatography (SiO2, CH2Cl2–2-PrNH2).
Spectral and Analytical Data for Selected Compounds
N-Phenyl-1,4-butanediamine (1a) was obtained as an oil
Spectral and analytical data of compounds 1b–h,j–l are
available as Supporting Information.
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