(cyanoethyl)amines using a very large molar excess of lithium
aluminum hydride in order to minimize secondary and tertiary
amine byproduct formation.6 The principal objective of the work
described here was to establish a more efficient preparation of
the triamines by use of a relatively low-pressure catalytic
hydrogenation procedure that would avoid formation of un-
wanted secondary and tertiary amine byproducts. Catalytic
hydrogenation of nitriles has been successfully employed under
high-pressure conditions to make dendrimers,16,17 but success
is not normally achieved under much lower pressures wherein
byproduct contamination is significant.17
A number of experimental procedures to decrease byproduct
formation during the hydrogenation have been reported. These
procedures include addition of ammonia7 and inorganic bases,
such as sodium hydroxide18,19 or lithium hydroxide,20 to the
solutions containing the nitriles to be reduced. Side reactions
may also be eliminated during hydrogenation by the direct
acylation of the product primary amine with acetic anhydride8
or by protonation with acid.21-24 Ammonia in the reaction
mixture is thought to reduce secondary and tertiary amine
formation by competing with the newly formed primary or
secondary amines, respectively, for conjugate addition to the
intermediate imine (B, Scheme 1) formed from the nitrile (A).25
In contrast, inorganic base is thought to selectively poison the
catalyst toward hydrogenolysis reactions and/or inhibit the
deposition of oligomeric secondary amines that block the active
sites on the catalyst.18 When a single nitrile is to be reduced,
catalytic hydrogenation can be accomplished in the presence
of variable concentrations of methanolic ammonia with mini-
mum byproduct formation.26-29 However, it has been reported
Preparation of N-Alkylbis(3-aminopropyl)amines
by the Catalytic Hydrogenation of
N-Alkylbis(cyanoethyl)amines
Travis T. Denton, Abigail S. Joyce, and Donald E. Kiely*
Shafizadeh Rocky Mountain Center for Wood and Carbohydrate
Chemistry, UniVersity of Montana, Missoula, Montana 59812
ReceiVed February 5, 2007
An improved process for the preparation of N-alkylbis(3-
aminopropyl)amines is described. These triamines are of
interest as monomers for the condensation polymerization
with esterified carbohydrate diacids (aldaric acids) to generate
the corresponding poly(4-alkyl-4-azaheptamethylene aldara-
mides). The triamine synthesis is comprised of two efficient
steps and requires no chromatographic purification. Biscon-
jugate addition of alkylamines to acrylonitrile followed by
catalytic hydrogenation of the N-alkylbis(cyanoethyl)amines
over Raney nickel yields the target N-alkylbis(3-aminopro-
pyl)amines. Much less solvent was used in the bisconjugate
addition step then previously reported, and in the second step,
a relatively low-pressure catalytic hydrogenation (50 psi of
hydrogen) was employed using Raney nickel as the catalyst
in a 7 N methanolic ammonia solvent system to afford the
N-alkylbis(3-aminopropyl)amines of high purity in nearly
quantitative yield.
(12) Bell, T. W.; Choi, H. J.; Harte, W.; Drew, M. G. J. Am. Chem.
Soc. 2003, 125, 12196-12210.
(13) Blaser, H.-U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner, H.; Studer,
M. AdV. Synth. Catal. 2003, 345, 103-151.
(14) Curtis, N. F.; Gladkikh, O. P.; Heath, S. L.; Morgan, K. R. Inorg.
Chim. Acta 2003, 242-244.
(15) Meijer, E. W.; Bosman, H. J. M.; Vandenbooren, F. H. A.; De
Brabander-van den Berg, E. M. M.; Castelijns, A. M. C. F.; De Man, H. C.
J.; Reintjens, R. W. E. G.; Stoelwinder, C. J. C.; Nijenhuis, A. J. Dendritic
macromolecule and the preparation thereof. U.S. Patent 5,530,092, 1996.
(16) Woerner, C.; Muelhaupt, R. Angew. Chem., Int. Ed. Engl. 1993,
32, 1306-1308.
The reduction of nitriles is a fundamental synthetic organic
transformation for the preparation of primary amines and is
commonly carried out with varying degrees of success using
lithium aluminum hydride1-6 or by catalytic hydrogenation
procedures.7-15 The target triamines in this report were previ-
ously prepared by reduction of the precursor N-alkylbis-
(17) De Brabander-van den Berg, E. M. M.; Meijer, E. W. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1308-1311.
(18) Thomas-Pryor, S. N.; Manz, T. A.; Liu, Z.; Koch, T. A.; Sengupta,
S. K.; Delgass, W. N. Chem. Ind. 1998, 75, 195-206.
(19) Allgeier, A. M.; Duch, M. W. Chem. Ind. 2001, 82, 229-239.
(20) Johnson, T. A.; Freyberger, D. P. Chem. Ind. 2001, 82, 201-227.
(21) Miller, E.; Sprague, J. M.; Kissinger, L. W.; McBurney, L. F. J.
Am. Chem. Soc. 1940, 62, 2099-2103.
(1) Zhu, J.; Quirion, J. C.; Husson, H. P. J. Org. Chem. 1993, 58, 6451-
6456.
(2) Cimino, G.; Gavagnin, M.; Sodano, G.; Spinella, A.; Strazzullo, G.;
Schmitz, F. J.; Yalamanchili, G. J. Org. Chem. 1987, 52, 2301-2303.
(3) Plenio, H.; Diodone, R. J. Org. Chem. 1993, 58, 6650-6653.
(4) Ruchelman, A. L.; Houghton, P. J.; Zhou, N.; Liu, A.; Liu, L. F.;
LaVoie, E. J. J. Med. Chem. 2005, 48, 792-804.
(5) Kalivretenos, A. G.; Nakanishi, K. J. Org. Chem. 1993, 58, 6596-
6608.
(22) Work, T. S. J. Chem. Soc. 1942, 426-429.
(23) Freifelder, M.; Ng, H. Y. J. Pharm. Sci. 1965, 54, 1204.
(24) Short, J. H.; Dunnigan, D. A.; Ours, C. W. Tetrahedron 1973, 29,
1931-1939.
(25) von Braun, J.; Blessing, G.; Zobel, F. Ber. Dtsch. Chem. Ges. 1923,
56B, 1988-2001.
(6) Carter, A.; Morton, D. W.; Kiely, D. E. J. Polym. Sci., Part A: Polym.
Chem. 2000, 38, 3892-3899.
(26) Yasuda, N.; Hsiao, Y.; Jensen, M. S.; Rivera, N. R.; Yang, C.; Wells,
K. M.; Yau, J.; Palucki, M.; Tan, L.; Dormer, P. G.; Volante, R. P.; Hughes,
D. L.; Reider, P. J. J. Org. Chem. 2004, 69, 1959-1966.
(27) Sun, M.; Zhao, C.; Gfesser, G. A.; Thiffault, C.; Miller, T. R.; Marsh,
K.; Wetter, J.; Curtis, M.; Faghih, R.; Esbenshade, T. A.; Hancock, A. A.;
Cowart, M. J. Med. Chem. 2005, 48, 6482-6490.
(7) De Bellefon, C.; Fouilloux, P. Catal. ReV.sSci. Eng. 1994, 36, 459-
506.
(8) Gould, F. E.; Johnson, G. S.; Ferris, A. F. J. Org. Chem. 1960, 25,
1658-1660.
(9) Bergeron, R. J.; Garlich, J. R. Synthesis 1984, 782-784.
(10) Chin, J.; Banaszczyk, M.; Jubian, V.; Zou, X. J. Am. Chem. Soc.
1989, 111, 186-190.
(28) McLean, T. H.; Chambers, J. J.; Parrish, J. C.; Braden, M. R.;
Marona-Lewicka, D.; Kurrasch-Orbaugh, D.; Nichols, D. E. J. Med. Chem.
2006, 49, 4269-4274.
(29) Gardner, R. A.; Kinkade, R.; Wang, C.; Phanstiel, O., IV. J. Org.
Chem. 2004, 69, 3530-3537.
(11) Brana, M. F.; Dominguez, G.; Saez, B.; Romerdahl, C.; Robinson,
S.; Barlozzari, T. Eur. J. Med. Chem. 2002, 37, 541-551.
10.1021/jo070245v CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/31/2007
J. Org. Chem. 2007, 72, 4997-5000
4997